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Hematopoietic, immunomodulatory and epithelial effects of interleukin-11 US Schwertschlag, WL Trepicchio, KH Dykstra, JC Keith, KJ Turner and AJ Dorner

Genetics Institute, Cambridge and Andover, MA 02140/01810, USA

Interleukin 11 (IL-11) is a pleiotropic cytokine with biological Introduction activities on many different cell types. Recombinant human IL- 11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown Interleukin 11 (IL-11) is a cytokine first identified as an activity effects on multiple hematopoietic cell types. Its predominant in an immortalized primate bone marrow stromal cell line and in vivo hematopoietic activity is the stimulation of peripheral cloned from a human fetal lung fibroblast cell line.1,2 The platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late human IL-11 complementary DNA (cDNA) encodes a protein progenitor cells to stimulate megakaryocyte differentiation and of 199 amino acids with a leader sequence of 21 AA and a maturation. rhIL-11 has been approved for the treatment of molecular mass of 19 kDa. The secreted protein has 178 chemotherapy-induced thrombocytopenia. The hematopoietic amino acids, is monomeric, and exhibits a pI Ͼ11. IL-11 inter- effects of rhIL-11 are most likely direct effects on progenitor acts with its ligand-specific cell surface receptor subunit (IL- cells and megakaryocytes in combination with other cytokines 11R␣) that is coupled to a signal transducing subunit, gp130.3 or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and IL-11 is a member of a family of cytokines, including IL-6, LIF, fibrinogen) from the liver. The induction of heme oxidase and Oncostatin M, CT-1 and CNTF that utilizes gp130 as the signal inhibition of several P450 oxidases have been reported from transducing subunit of the receptor complex and, thus, exhibit in vitro studies. In vivo, rhIL-11 treatment decreases sodium some overlapping activities. IL-11R␣ is found on numerous excretion by the kidney by an unknown mechanism and tissues.4,5 IL-11 mRNA expression is also ubiquitous, but induces hemodilution. rhIL-11 also exhibits anti-inflammatory blood IL-11 levels are rarely detected.6–8 Interleukin-11 is a effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflam- pleiotropic cytokine that displays diverse effects such as matory skin disease, autoimmune joint disease, and various stimulation of myeloid, erythroid and megakaryocyte differen- infection-endotoxemia syndromes. rhIL-11 has trophic effects tiation as well as modulation of macrophage and T cell on non-transformed intestinal epithelium under conditions of inflammatory function and induction of the hepatic acute mucosal damage. The mechanism of the anti-inflammatory phase response.9,10 activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF␣), interleukin 1␤ (IL-1␤), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition IL-11 gene structure of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-␬B). The block to NF-␬B nuclear translocation cor- The genomic sequence for IL-11 is contained on a 7 kb frag- relates with the ability of rhIL-11 to maintain or enhance pro- ment. The human gene consists of five exons and four introns duction of the inhibitors of NF-␬B, I␬B-␣ and I␬B-␤. In addition and maps to human chromosome 19q13.3–19q13.4.11 The IL- to effects on macrophages, rhIL-11 also reduces CD4؉ T cell 11 promoter contains consensus nucleotide binding sites for production of Th1 cytokines, such as IFN␥ induced by IL-12, transcription factors AP-1, SP-1, CTF/NF-1 and EF/C. In while enhancing Th2 cytokine production. rhIL-11 also blocks addition, interferon-inducible and phorbol-ester-inducible IFN␥ production in vivo. The molecular effects of rhIL-11 have elements have been localized to the 5Ј region of the gene. A also been studied in a clinical trial. Molecular analysis of skin ␬ biopsies of patients with psoriasis before and during rhIL-11 putative NF- B binding element has been localized 720 bp treatment demonstrates a decrease in mRNA levels of TNF␣, upstream of the mRNA start site.12 Two polyadenylation sig- IFN␥ and iNOS. These activities suggest that in addition to its nals have been identified at the 3Ј end of the gene leading thrombopoietic clinical use, rhIL-11 may also be valuable in the to the production of two transcripts that differ only in the 3Ј treatment of inflammatory diseases. The clinical utility of the untranslated sequences. anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn’s disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and main- -tained by activated CD4؉ Th1 cells in conjunction with acti vated macrophages. IL-11 protein Keywords: rhIL-11 Structurally, IL-11 is unrelated to any other cytokine and displays a number of distinct protein features such as an absence of cysteine residues, asparagine-linked glycosylation sites, and O-linked glycosylation. IL-11 is rich in proline (12%), leucine (23%) and other positively charged residues (14%), resulting in a highly basic protein with an isoelectric point of Ͼ11. Recombinant human IL-11 (rhIL-11) is manufactured in E. coli Correspondence: US Schwertschlag; Fax: 617-665-8854 and differs from the naturally occurring molecule in the Received 6 April 1999; accepted 31 May 1999 absence of the amino terminal proline residue.13,14 Review US Schwertschlag et al 1308 Gene expression IL-11 binding to the IL-11R␣ chain alone occurs with low affinity (kd ෂ 10 nM) and is insufficient to transduce a signal. Little is known regarding regulation of IL-11 expression in A high affinity receptor complex capable of transducing a sig- vivo. Analysis of normal adult murine tissue indicates the pres- nal (kd ෂ400–800 pM) is generated upon co-expression of IL- ence of low levels of IL-11 mRNA in the thymus, spleen, bone 11R␣ and gp130.5,27 The stoichiometry of the high affinity IL- marrow, heart, lung, small and large intestine, kidney, brain, 11R complex is at present unknown. Recent evidence from in testis and ovary.4,15 In situ hybridization has localized IL-11 vitro solution phase binding assays indicates that the high expression to the middle cellular layers of the seminiferous affinity IL-6R consists as a hexameric complex of two IL-6 tubules of the testis and the hippocampus and ventral area of molecules, two IL-6R␣ chains, and a gp130 homodimer. A the spinal cord.15 Detection of IL-11 in the blood of humans similar hexameric complex has also been proposed for the or animals is rare, suggesting that synthesis and secretion CNTFR complex, with the exception of a heterodimer of occur at a low level. Alternatively, because of its highly basic gp130 and the LIFR ␣ chain replacing the gp130 homodimer. nature, IL-11 may bind to extracellular matrix and remain Similar studies examining the IL-11R complex indicate a localized near the cellular site of synthesis. dimer of IL-11 and IL-11R␣ forms in the presence of gp130, resulting in a pentameric complex. However, homodimeriz- ation of gp130 or heterodimerization of gp130 and LIFR did IL-11 receptor not occur.26 These studies suggest an as yet unidentified IL-11R ␣-chain involved in IL-11 signal transduction. The IL-11 receptor complex consists of the ligand binding ␣ Biological functions essential to IL-11 have been investi- chain and the signal transducing subunit, gp130.5 IL-11 shares gated through the generation of mice with a null mutation of the utilization of gp130 with IL-6, LIF, Oncostatin M and the IL-11R ␣-chain gene (IL-11R␣−/−).28–30 IL-11R␣−/− mice CNTF which results in partly overlapping activities.3 IL-11R␣ were healthy and had normal peripheral white blood cell, chain consists of an extracellular domain, containing two hematocrit and platelet levels.28 However, female mice were potential N-linked glycosylation sites, a transmembrane infertile because of defective decidualization.29,30 Thus, domain, and a cytoplasmic tail.5,16,17 Primary amino acid similar to LIF, IL-11 appears to play a critical role during comparisons indicate that IL-11R␣ is most closely related to reproduction. Together, these ligands comprise a family of IL-6R␣ chain (24% amino acid homology) and CNTF receptor structurally related proteins that share many overlapping func- ␣ chain (22% amino acid homology). The extracellular tional properties because of a shared receptor signaling domain contains structural features characteristic of hemato- complex. poietic receptors such as proline residues preceding each 100 amino acid subdomain, a motif of four conserved cysteines and one tryptophan residue, a series of polar and hydrophobic Regulation of IL-11 secretion amino acid residues, and the WSXWS domain between the cysteine and transmembrane domain. IL-11 protein secretion and/or gene expression is induced by ␣ ␣ ␣ ␤ The genomic structure of the murine IL-11R consists of 14 IL-1 , TNF- , TGF- , prostaglandin E2 (PGE2), parathyroid exons with alternative use of the first two exons being devel- hormone, 1,25-dihydroxyvitamin D3, phorbol myristate acet- opmentally regulated.18 More recently, a second murine IL- ate (PMA), the calcium ionophore A23187, and a variety of 11R␣ locus has been identified (IL-11R␣ 2) adjacent to the IL- viruses (such as respiratory syncytial, parainfluenza and rhino- 11R␣ 1 gene.19 It shares 99% sequence identity with IL-11R␣ virus) in cells primarily of mesenchymal origin.31–34 IL-11 1 in the coding exons but contains differences in the 5Ј expression has been detected in a number of in vitro cell cul- untranslated region (5ЈUTR). The murine IL-11R␣ 1 gene is ture assays, including fibroblasts, chondrocytes, synoviocytes, expressed at relatively low abundance in a broad spectrum of osteoblasts and trophoblasts.35–37 tissues including bone marrow, spleen, thymus, lung, bladder, heart, brain, kidney, muscle, salivary gland, small and large intestine, ovary, testis and uterus as well as a number of pri- Endogenous IL-11 protein levels mary cell types such as macrophages, osteoblasts and osteoclasts.4,20,21 Expression of the IL-11R␣ 2 gene is restricted to Endogenous IL-11 plasma or serum concentrations are unde- the testis, lymph node and thymus.19 The human IL-11R␣ tectable or at very low levels in normal volunteers or patients chain shares 85% nucleotide identity and 84% amino acid undergoing bone marrow transplantation.6,38 It has also been identity with the murine genes.17,22 Its genomic structure con- concluded that circulating levels of IL-11 do not contribute to sists of 12 exons contained on a 9-kb region and is located a major extent to liver acute phase protein production.39 IL- on chromosome 9 band 9p13.23 Two isoforms of the human 11 has been found in synovial fluid and in human ovarian ␣ chain have been identified which differ in the structure of follicular fluid.7 The function of IL-11 in these compartments their cytoplasmic domains.24 One isoform has a short cyto- has been linked to its anti-inflammatory activity and involve- plasmic domain similar to the IL-6R␣ and murine IL-11R␣ ment in follicular maturation. chains. The second isoform lacks the cytoplasmic domain and is more similar to the human CNTF receptor (CNTFR). The structural similarities between the ␣ chains of IL-11R and Hematopoietic effects of IL-11 CNTFR suggest that they may have evolved from a common ancestor. A transcript encoding a soluble form of IL-11R␣ has In vitro hematopoietic effects been identified, no soluble IL-11R␣ protein has been found.25 The IL-11R␣ chain does not have to be membrane bound to Early studies demonstrated the hematopoietic effects of rhIL- elicit a biological effect because recombinant soluble forms 11 in an in vitro blast colony assay to enhance the number of the ␣-chain receptor have been generated in vitro that can of blast cell colonies.40,41 In synergy with other early acting bind IL-11 and activate gp130.26 hematopoietic growth factors such as IL-3, IL-4 or stem cell Review US Schwertschlag et al 1309 factor, IL-11 can trigger division of quiescent primitive pro- Platelet growth dynamics genitor cells by stimulating exit from the G0 phase and the entry into G1/S phase of the cell cycle. IL-11 also has direct A phase I study in patients with breast cancer showed that effects on megakaryocytes (MK) and MK precursors in vitro.42 treatment with rhIL-11 before chemotherapy resulted in a In synergy with IL-3, IL-11 enhanced both murine and human dose-dependent increase in platelet levels.51 Following a MK colony formation. These in vitro studies have indicated small decrease (probably due to hemodilution caused by rhIL- that rhIL-11 acts on both early- and late-stage progenitor cells 11), platelet levels rose above baseline 5 days after the start to promote megakaryocyte differentiation and maturation. of treatment and continued to rise throughout the 14-day treat- rhIL-11 also stimulates erthyropoiesis and lymphopoiesis in ment period. At doses of 10, 25, 50 and 75 ␮g/kg, platelet vitro. In synergy with Steel Factor and erthyropoietin, rhIL-11 levels achieved maximum levels 76, 93, 108 and 186% above stimulated early stage erythroid burst formation.43 In combi- baseline at a median 18, 19, 16 and 14 days, respectively, nation with IL-3, rhIL-11 stimulated the development of hemo- after the start of treatment. rhIL-11 resulted in no apparent globinized bursts, indicating effects on late stage erythroid changes in platelet function. In a study of the efficacy of rhIL- development. rhIL-11 has been shown to stimulate antibody 11 for prevention of severe chemotherapy-induced throm- producing B cells in an accessory cell-dependent manner.44 bocytopenia, patients treated daily with 50 ␮g/kg rhIL-11 following chemotherapy were significantly less likely to require a platelet transfusion than those treated with placebo.52 Kinetic analysis of platelet profiles54 suggested that treatment with In vivo hematopoietic effects rhIL-11 had no effect on average platelet lifetime but resulted in higher predicted platelet nadirs (21 ± 16 vs 14 ± 8 × 103/␮l, In all species tested (mouse, rat, dog, hamster and nonhuman P = 0.014 reduced the amount of time required for the platelet primate), rhIL-11 increased peripheral platelet counts when level to return to 50 000 cells/␮l (17 ± 5 vs 19 ± 4 days, administered as a single agent to normal animals.45–47 Normal P = 0.089) compared with placebo. mice and rats administered rhIL-11 for 7 days, had a 30% to 50% elevation in peripheral platelets. Studies in nonhuman primates also showed that rhIL-11 increased peripheral Epithelial effects platelet counts. In rhIL-11-treated cynomolgus monkeys, bone marrow megakaryocytes appeared to be mature and ultra- Epithelial cells in vitro structurally normal.48 These animal studies indicate that one of the predominant in vivo effects of rhIL-11 is the stimulation rhIL-11 directly interacts with intestinal epithelial cells to of multiple phases of megakaryocytopoiesis and thrombopo- inhibit proliferation in vitro.55,56 Treatment of rat intestinal epi- iesis. thelial cell lines (IEC-6 and IEC-18) with rhIL-11 resulted in In murine models of chemotherapy- and/or irradiation- inhibition of proliferation. Growth inhibition correlated with induced myelosuppression or bone marrow transplantation delayed entry into the S phase of the cell cycle and sup- subsequent to myeloablation, administration of rhIL-11 stimu- pression of retinoblastoma protein (pRB) phosphorylation.56 lated megakaryocytopoiesis, thrombopoiesis, and multi- These studies indicate that rhIL-11 can directly affect intestinal lineage recovery of hematopoietic progenitor cells.49 In epithelial cells. addition, in a carboplatin model of myelosuppression in cynomolgus monkeys, once daily treatment with rhIL-11 improved platelet nadirs and accelerated platelet recovery compared In vivo models of epithelial damage with control animals.45,50 The multilineage stimulation of rhIL- 11 in these myeloablated animals probably represents synergy In a murine model of combined chemotherapy and radiation with endogenous cytokines, induced by the myeloablative in which death occurred from sepsis secondary to gastrointes- regimens. Taken together, these observations suggest that nor- tinal damage, rhIL-11 treatment ameliorated small intestinal mal physiological processes of megakaryocyte development damage and increased survival.57 In a follow-up study, ani- and thrombopoiesis were induced by rhIL-11. mals treated with rhIL-11 showed reduced apoptosis and increased mitosis in the small intestine, which was associated with mucosal recovery from cytoablative damage.58 In a hamster model of 5-FU-induced oral mucositis, administration of Clinical cancer support therapies rhIL-11 reduced the severity, frequency, and duration of oral mucositis.59,60 Taken together, these studies suggest that rhIL- The use of rhIL-11 as a supportive therapy for the prevention 11 may have multiple effects on the gastrointestinal epi- of severe thrombocytopenia following cancer chemotherapy thelium, depending on the state of the tissue. rhIL-11 may has been evaluated in several clinical trials. The results indi- block the proliferation of normal undamaged epithelial cells cate that rhIL-11 treatment produced a dose-dependent and so protect from cytotoxic damage while enhancing increase in peripheral platelets, which reduced the need for proliferation following injury. platelet transfusions.51,52 As a result of these trials, rhIL-11 is In a murine model of bowel ischemia, pretreatment with IL- currently marketed (Neumega; Genetics Institute, Andover, 11 decreased mortality and morbidity.61 In a murine model of MA, USA) for the treatment of chemotherapy-induced throm- short bowel syndrome, treatment with IL-11 ameliorated the bocytopenia. The clinical experience indicates that about 1% nutritional deficits of decreased absorptive capacity by stimul- of patients treated with Neumega develop antibodies, with no ating intestinal epithelial growth and function.62,63 These data noticeable impact on its activity, thus these antibodies seem suggest that IL-11 has a trophic effect on small intestinal to be non-neutralizing. Based on its effects on damaged epi- enterocytes, causing cell proliferation and increased mucosal thelium (as described in the next section), rhIL-11 is also cur- thickness. Epidermal growth factor, which was used for com- rently under investigation for the treatment of mucositis.53 parison, has a more generalized effect on intestine causing Review US Schwertschlag et al 1310 proliferation of both enterocytes and myocytes. These in vivo Adipocytes and osteoclasts findings seem to be in contradiction to the cell cycle inhibition seen in the in vitro studies. Most probably this reflects the interaction of different cytokines and growth factors in rhIL-11 has been shown to block adipogenesis in a murine stromal cell line H-1/A and in a murine preadipocyte cell line vivo, when the mucosal epithelium is damaged. Taken 68,69 together, the effect of rhIL-11 on damaged epithelium may be 3T3-11. The inhibitory effect of IL-11 on adipogenesis is believed to be mediated by IL-11 via the activation of Src- to promote proliferation and so accelerate healing. In family protein tyrosine kinases and phosphatidylinositol 3-kin- addition, maintenance of gastrointestinal integrity protects the 70 organism from bacterial translocation. ase in 3T3-L1 mouse preadipocytes. rhIL-11 increases the number of osteoclasts and raises the calcium concentration in the medium of neonatal murine calvaria organ culture.71 In a calvaria culture system, IL-11-mediated bone resorption was identified as operating through PGE and was inhibited by Acute phase response 2 cyclooxygenase inhibitors (eg indomethacin, NS-398 and

dexamethasone). The addition of exogenous PGE2 overcame In vitro hepatocytes the inhibitory effect of cyclooxygenase inhibitors and pro- moted bone resorption.72 However, when tested in ovariectomized rats, rhIL-11 did not have deleterious effects on bone rhIL-11 has been shown to induce gene expression in hepato- mineral density or bone remodeling.73 IL-11 may contribute cyte cell lines and primary rat hepatocyte cultures. Treatment to the maintenance of a bone marrow microenvironment in of primary rat hepatocytes and a rat hepatoma cell line, H- affecting structural, nutritional, and proliferative systems. 35, with rhIL-11 induced the production of type 2 acute phase ␣ 64 proteins, including thiostatin, fibrinogen, and 1-antitrypsin. Dexamethasone synergized with rhIL-11 to increase the production of the type 2 acute phase proteins. rhIL-11 also Chondrocytes and synoviocytes enhanced the IL-1-induced production of the type 1 acute ␣ phase proteins, including complement C3, 1-acid glyco- protein, haptoglobin, and hemopexin. In other studies, rhIL- The capacity of isolated rheumatoid synovial cells (RSC) to 11 treatment of primary cultures of rat hepatocytes induced produce IL-11, and the effect of indomethacin, dexame- the expression of tissue inhibitor of metalloproteinase-1 thasone and IFN-␥ on IL-11 production in RSC was studied in (TIMP-1) and metallothionein.65 Matrix metalloproteinases are cell cultures.74 The results suggest that the production of IL- involved in tissue destruction during inflammation. Metallo- 11 by rheumatoid synovia was differentially regulated by thionein is a cysteine-rich metal-binding protein which is PGE2 and IFN-␥. Treatment of the RSC cultures with indome- induced early during an acute phase response. Elevated levels thacin or dexamethasone decreased the level of IL-11 pro- of metallothionein may function to sequester zinc from the duction. IL-11 has also been shown to be produced in arthritic plasma and so limit zinc loss from damaged tissues. Treatment synovial tissue culture.75 Neutralization of IL-11 activity with of the human hepatoma cell line, HepG2, increased the levels antibody increased the production of TNF␣ and inhibition of of heme oxygenase mRNA.66 Heme oxygenase, the rate limit- IL-11 and IL-10 increased TNF␣ production greater than inhi- ing enzyme in heme catabolism, has been implicated in pro- bition of either cytokine alone. rhIL-11 has also been shown to tection against oxidative stress and resolution of acute increase tissue inhibitor of metalloproteinase-1 (TIMP-1) from inflammation. human articular chondrocytes and synoviocytes.35 These results suggest that IL-11 may play a protective role in joint destruction during inflammatory disease.

Acute phase response in vivo

Macrophages Serum concentrations of acute phase proteins (fibrinogen, c- reactive protein, ferritin and haptoglobin) increase in patients and normal volunteers treated with IL-11. In breast cancer In addition to its hematopoietic activities, IL-11 can down- patients given varying doses of rhIL-11 for 14 days (10, 25, regulate macrophage effector function through the inhibition 50 and 75 ␮g/kg/day), fibrinogen and CRP were substantially of TNF-␣, IL-1␤, IL-12, and NO production.76–78 The anti- increased relative to baseline 96 h after the first dose. Levels inflammatory activity of rhIL-11 on activated macrophages is of both acute phase reactants returned close to baseline levels due, in part, to suppression of pro-inflammatory cytokine gene 7 days after the last rhIL-11 dose.51 Similarly, normal volun- expression.21,78 This inhibition correlates with a block to teers given 25 ␮g/kg/day for 7 days experienced increased nuclear translocation of NF-␬B, a transcription factor, and an fibrinogen, haptoglobin and von Willebrand levels relative to increase in the cytoplasmic levels of the NF-␬B inhibitory pro- baseline within 72 h of the first rhIL-11 dose.67 In patients with teins, I␬B-␣ and I␬B-␤.21 The biological activity of rhIL-11 on Crohn’s disease treated once or twice weekly with rhIL-11 for macrophages is direct and independent of other anti-inflam- 3 to 6 weeks, fibrinogen levels initially increased and then matory molecules such as IL-10 and TGF-␤1. Consistent with decreased during continued dosing. Thus, the effects of the in vitro data, in an in vivo murine model of endotoxemia, exogenous rhIL-11 on acute phase protein secretion are com- rhIL-11 also down-regulated serum levels of LPS-induced pro- plex, not well understood, and may not reflect the role of inflammatory cytokines, including TNF␣ and IL-1␤.76 Thus, endogenous IL-11. These findings indicate that one response similar to but distinct from IL-10 and TGF-␣␤, rhIL-11 acts as of the liver to rhIL-11 treatment is the production of a multi- an anti-inflammatory cytokine through modulation of macro- tude of homeostatic and cyto-protective proteins. phage effector cell function. Review US Schwertschlag et al 1311 Neutrophils 11 had a trophic effect as measured by villus height and crypt cell mitosis.62,63 IL-11 accelerates recovery of peripheral blood neutrophils and Studies in transgenic animals over-expressing IL-11 in the platelets in rodents, normal volunteers, and patients lung demonstrated that IL-11 markedly diminishes hyperoxic recovering from chemotherapy.79 rhIL-11 does not affect the lung injury. The observed protection was associated with functions of purified human neutrophils in vitro.80 This sug- small changes in lung antioxidants, diminished hyperoxia- gests that treatment with rhIL-11 will not compromise innate induced IL-1␣ and TNF␣ production, and markedly sup- immunity. pressed hyperoxia-induced DNA fragmentation.88 In a murine model of radiation-induced thoracic injury, rhIL-11 treatment increased survival and reduced TNF␣ expression in the lung.77 In a murine model of graft-versus-host disease (GVHD), rhIL- B cells and T cell (lymphocytes) 11 prevented acute GVHD and polarized the T cell response to a TH2 phenotype.89 rhIL-11 reduced serum levels of IFN␥ In murine spleen cultures, rhIL-11 increased the number of and TNF␣ while preventing small bowel damage. clones producing sheep red blood cell-specific antibody.1,44 + + In a murine model of toxic shock syndrome, pretreatment Depletion of CD4 but not CD8 helper T cells completely with rhIL-11 before administration of a lethal dose of S. aureus abrogated the ability of rhIL-11 to enhance the antibody enterotoxin B galactosamine protected against mortality.90 response, suggesting that stimulation was mediated at least in Pretreatment with rhIL-11 reduced serum levels of pro- part, indirectly through effects on T cells. In primary cultures inflammatory cytokines, including TNF␣, IL-1␣ and IFN-␥, of bone marrow derived from 5-FU-treated mice, rhIL-11 in following LPS administration in a murine model of combination with SCF or IL-4 supported the maintenance of endotoxemia.76 In a rabbit model of endotoxemia, rhIL-11 B lymphoid potential. IL-4 in combination with rhIL-11 administration prevented LPS-induced hypotension and reversed the inhibition of early B cell development by IL-3 in 91 81 gastrointestinal damage. primary bone marrow cultures. In a human culture system, The biological activity of rhIL-11 has been studied in a rat rhIL-11 had no effect on purified B cells or B cells stimulated model of gram-negative sepsis.92 In this model, which mimics with a T cell-independent B cell mitogen. However, rhIL-11 the clinical situation of infection following myelosuppressive enhanced IgM and IgG production when B cells were cultured therapy, rats are colonized with Pseudomonas aeruginosa and with T cells, monocytes and pokeweed mitogen.82 These rendered neutropenic by treatment with cyclophosphamide. results suggest that rhIL-11 can promote accessory cell- rhIL-11 was administered following the onset of fever. Treat- dependent B cell differentiation. In a murine model of T cell ment with rhIL-11 increased survival from 0% in vehicle- differentiation, rhIL-11 polarized differentiation to the Th 2 treated animals to 40%. When rhIL-11 was given in combi- phenotype (Trepicchio, WL et al, unpublished). rhIL-11 nation with an antimicrobial agent, ciprofloxin, survival rose increased secretion of IL-4 and IL-5 and decreased secretion from 60% with ciprofloxin treatment alone to 100% with of IL-12. combination therapy. rhIL-11-treated animals had reduced quantitative levels of bacterial infection in the lung, reduced intestinal mucosal damage, and reduced serum levels of TNF␣ Models of inflammation compared with vehicle-treated animals. Taken together, these studies suggest that rhIL-11 treatment may ameliorate a sys- The ability of rhIL-11 to attenuate pro-inflammatory cytokine temic inflammatory response and associated tissue damage by production, modulate the immune and acute phase response, effects on both macrophage and T cell effector functions. and promote mucosal repair correlates with its ability to reduce inflammation and tissue damage in a variety of experimental animal models of acute and chronic inflammatory Kidney bowel disease and systemic inflammation. rhIL-11 treatment reduces the clinical signs and histologic lesions of chronic col- IL-11 may have direct effects on renal solute and water trans- itis in transgenic rats expressing the human major histocom- port. IL-11 causes volume retention within 5 to 8 h after sub- patibility complex (MHC) class I allele, HLA-B27.83 RT-PCR cutaneous injection. In an isolated perfused kidney system, it analysis of colonic RNA revealed that treatment with rhIL-11 was demonstrated that IL-11 was almost completely filtered down-regulated expression of pro-inflammatory cytokines by glomerular filtration and reabsorbed by the kidney.93 It is including TNF-␣, IL-1␤ and IFN-␥.84 rhIL-11 also reduced the thus conceivable that IL-11 is metabolized and inactivated level of myeloperoxidase activity in the cecum, indicating by the kidney. It is unclear at present whether the effect of reduced inflammation. After stimulation in vitro with anti-CD3 IL-11 on salt and water homeostasis is a direct effect of IL-11 antibody, spleen cell cultures derived from rhIL-11-treated rats on the kidney or an indirect effect activated through a cardio- produced less IFN-␥, TNF-␣ and IL-2 than cultures derived vascular mechanism. from vehicle-treated rats.84 These molecular and cellular effects correlated with the amelioration of disease, as measured by stool character and histologic lesion scores. Treatment Clinical studies with rhIL-11 also modulates acute colonic injury in the acetic acid-induced colitis mode85 and TNBS-induced colitis.86,87 Clinical pharmacology and rhIL-11 disposition Additional animal studies have demonstrated the effects of rhIL-11 on intestinal mucosa, following bowel ischemia and The clinical pharmacology of rhIL-11 has been studied in nor- in a model of short bowel syndrome. In a murine model of mal volunteers and patients. rhIL-11 is rapidly eliminated after ischemic bowel necrosis, prophylactic treatment with rhIL-11 intravenous injection (t1/2 between 1.5 and 2 h). Subcutane- decreased mortality and enhanced recovery of the intestinal ously administered rhIL-11 exhibits an absorption-limited dis- mucosa.61 Following 90% resection of the small bowel, rhIL- position, with a mean residence time between 10 and 15 h. Review US Schwertschlag et al 1312 The bioavailability of rhIL-11 is between 60 and 80%.94 rhIL- rhIL-11 is associated with induction of an acute phase 11 is predominantly cleared renally, as indicated by a 60% response, including elevation of fibrinogen and von Wille- increase in area under the curve (AUC) in dialysis patients95 brand factor. Based on this assessment, rhIL-11 should and animal experiments that demonstrate both renal filtration offer multiple benefits for patients treated with cytoablative and tubular reabsorption of rhIL-11.93 therapies and prove of clinical value in the therapy of In patients and normal volunteers, IL-11 was found to cause inflammatory diseases. a dilutional anemia, which was reversible upon cessation of treatment. Volume retention was demonstrated in normal volunteers as a result of renal sodium retention. Whether this Acknowledgements effect reflects a direct renal mechanism of rhIL-11 or is mediated via other sodium-conserving mechanisms (eg the The assistance of Kit O’Kelly, Liz McKinlay and Melinda renin-angiotensin system) is unclear at this time.96,97 The kid- Burke is gratefully acknowledged. ney is also the major pathway of IL-11 clearance; IL-11 is removed by glomerular filtration and completely reabsorbed at the proximal tubule. The function of IL-11 at the proximal References tubule is unknown and may be a general tubular protein conserving mechanism. Dialysis-dependent humans and 1 Paul SR, Bennett F, Calvetti JA, Kelleher K, Wood CR, O’Hara RM Anephric experimental animals have a delayed clearance of Jr, Leary AC, Sibley B, Clark SC, Williams DA, Yang Y-C. Molecu- rhIL-11.95 lar cloning of a cDNA encoding interleukin 11, a stromal cell- derived lymphopoietic and hematopoietic cytokine. Proc Natl Acad Sci USA 1990; 87: 7512–7516. 2 Paul SR, Schendel P. The cloning and biological characterization Inflammatory disease of recombinant human interleukin-11. Int J Cell Cloning 1992; 10: 135–143. rhIL-11 is currently under investigation for a variety of 3 Taga T. The signal transducer gp130 is shared by interleukin-6 inflammatory conditions including Crohn’s disease,98 rheuma- family of haematopoietic and neurotrophic cytokines. Ann Med toid arthritis and psoriasis. In these clinical studies, rhIL-11 is 1997; 29: 63–72. 4 Davidson AJ, Freeman S-A, Crosier KE, Wood CR, Crosier PS. given subcutaneously once or twice per week for up to 3 Expression of murine interleukin 11 and its receptor alpha-chain months. The results of these studies have been encouraging in adult and embryonic tissues. Stem Cells 1997; 15: 119–124. and have led to later phases of development. 5 Hilton DJ, Hilton AA, Raicevic A, Rakar S, Harrison-Smith M, Gough NM, Begley CG, Metcalf D, Nicola NA, Willson TA. Clon- ing of a murine IL-11 receptor ␣-chain; requirement for gp130 for Summary high affinity binding and signal transduction. EMBO J 1994; 13: 4765–4775. 6 Wang JC, Chen C, Lou L-H, Mora M. Blood thrombopoietin, IL- Many studies have identified the pleiotropic properties of rhIL- 6 and IL-11 levels in patients with agnogenic myeloid metaplasia. 11. IL-11 is secreted by mesenchymal cells in the bone mar- Leukemia 1997; 11: 1827–1832. row microenvironment, with direct effects on hematopoietic 7 Branisteanu I, Pijnenborg R, Spiessens C, Van der Auwera I, Keith precursor cells, macrophages, adipocytes, epithelial cells and JC Jr, Van Assche FA. Detection of immunoreactive interleukin-11 T cells. rhIL-11 induces acute phase protein secretion from the in human follicular fluid: correlations with ovarian steroid, insulin- like growth factor I levels, and follicular maturity. Fertil Steril liver, which may contribute to its anti-inflammatory activity in 1997; 67: 1054–1058. vivo. In models of systemic inflammatory response, rhIL-11 8 Chang M, Williams A, Ishizawa L, Knoppel A, Van de Ven C, reduced the production of pro-inflammatory cytokines and Cairo MS. Endogenous interleukin-11 (IL-11) expression is increased survival. In models of acute gastrointestinal mucosal increased and prophylactic use of exogenous IL-11 enhances plat- injury, rhIL-11 increased survival and reduced mucosal dam- elet recovery and improves survival during thrombocytopenia age. rhIL-11 ameliorated gross and histologic damage in mod- associated with experimental group B streptococcal sepsis in neonatal rats. Blood Cells Mol Dis 1996; 22: 57–67. els of acute and chronic colitis. rhIL-11 has direct effects on 9 Schendel P, Turner K. Interleukin-11. In: Cytokines. Academic intestinal epithelial cells to modulate growth and gene Press, 1998, pp 169–182. expression. Several in vivo models have shown that rhIL-11 10 Dorner AJ, Goldman SJ, Keith JC Jr. Interleukin-11: biological has trophic effects and can reduce apoptosis in damaged activity and clinical studies. BioDrugs 1997; 8: 418–429. intestinal epithelium, resulting in protection and healing of the 11 McKinley D, Wu Q, Yang-Feng T, Yang Y-C. Genomic sequence mucosa. Maintenance of gastrointestinal mucosal integrity and chromosomal location of human interleukin-11 (IL11). Gen- omics 1992; 13: 814–819. reduces the risk of bacterial translocation and sepsis. The anti- 12 Bitko V, Velazquez A, Yang L, Yang YC, Barik S. Transcriptional inflammatory activity of rhIL-11 acts at multiple levels of the induction of multiple cytokines by human respiratory syncytial inflammatory response. rhIL-11 has direct effects on activated virus requires activation of NF-␬B and is inhibited by sodium sal- macrophages to reduce the production of pro-inflammatory icylate and aspirin. Virology 1997; 232: 369–378. cytokines, including TNF␣ and IL-1␤. Modulation of macro- 13 Czupryn MJ, McCoy JM, Scoble HA. Structure–function relation- phage function is mediated through inhibition of the transcrip- ships in human interleukin-11: identification of regions involved ␬ ␬ in activity by chemical modification and site-directed tion factor NF- B. NF- B is involved in the transcriptional mutagenesis. J Biol Chem 1995; 270: 978–985. activation of genes for many pro-inflammatory cytokines and 14 Czupryn M, Bennett F, Dube J, Grant K, Scoble H, Sookdeo H, adhesion molecules. Because of this, NF-␬B is considered to McCoy JM. Alanine-scanning mutagenesis of human interleukin- play an important role in many inflammatory diseases and has 11: identification of regions important for biological activity. Ann become a target of anti-inflammatory therapies. rhIL-11 also NY Acad Sci 1995; 762: 152–164. has direct effects on hepatocyte gene expression to produce 15 Du X, Everett ET, Wnat G, Lee W-H, Yang Z, Williams DA. Murine interleukin-11 (IL-11) is expressed at high levels in the hippocam- proteins important for homeostasis and tissue protection. In pus and expression is developmentally regulated in the testis. J hepatocyte culture, rhIL-11 induces expression of acute phase Cell Physiol 1996; 168: 362–372. proteins, TIMP-1, and heme oxygenase. In vivo treatment with 16 Neuhaus H, Bettenhausen B, Bilinski P, Simon-Chazottes D, Review US Schwertschlag et al 1313 Guenet J-L, Gossler A. Etl2, a novel putative type-I cytokine recep- production of the tissue inhibitor of metalloproteinases. J Biol tor expressed during mouse embryogenesis at high levels in skin Chem 1993; 268: 21527–21532. and cells with skeletogenic potential. Dev Biol 1994; 166: 531– 36 Suen Y, Chang M, Lee SM, Buzby JS, Cairo MS. Regulation of 542. interleukin-11 protein and mRNA expression in neonatal and 17 Van Leuven F, Stas L, Hilliker C, Miyake Y, Bilinski P, Gossler A. adult fibroblasts and endothelial cells. Blood 1994; 84: 4125– Molecular cloning and characterization of the human interleukin- 4134. 11 receptor alpha-chain gene, IL11RA, located on chromosome 37 Elias JA, Tang W, Horowitz MC. Cytokine and hormonal stimu- 9p13. Genomics 1996; 31: 65–70. lation of human osteosarcoma interleukin-11 production. Endo- 18 Bilinski P, Hall MA, Neuhaus H, Gissel C, Heath JK, Gossler A. crinology 1995; 136: 489–498. Two differentially expressed interleukin-11 receptor genes in the 38 Chang M, Suen Y, Meng G, Buzby JS, Bussel J, Shen V, Van DVC, mouse genome. Biochem J 1996; 320: 359–363. Cairo MS. Differential mechanisms in the regulation of endogen- 19 Robb L, Hilton DJ, Brook-Carter PT, Begley CG. Identification of ous levels of thrombopoietin and interleukin-11 during throm- a second murine interleukin-11 receptor alpha-chain gene bocytopenia: insight into the regulation of platelet production. (IL11Ra2) with a restricted pattern of expression. Genomics 1997; Blood 1996; 88: 3354–3362. 40: 387–394. 39 Gabay C, Singwe M, Genin B, Meyer O, Mentha G, Le CC, 20 Romas E, Udagawa N, Zhou H, Tamura T, Saito M, Taga T, Hilton Vischer T, Guerne P-A. Circulating levels of IL-11 and leukaemia DJ, Suda T, Ng KW, Martin TJ. The role of gp130-mediated signals inhibitory factor (LIF) do not significantly participate in the pro- in osteoclast development: regulation of interleukin 11 production duction of acute-phase protein by the liver. Clin Exp Immunol by osteoblasts and distribution of its receptor in bone marrow cul- 1996; 105: 260–265. tures. J Exp Med 1996; 183: 2581–2591. 40 Musashi M, Clark SC, Sudo T, Urdal DL, Ogawa M. Synergistic 21 Trepicchio WL, Wang L, Bozza M, Dorner AJ. IL-11 regulates interactions between interleukin-11 and interleukin-4 in support macrophage effector function through the inhibition of nuclear of proliferation of primitive hematopoietic progenitors of mice. factor-␬B. J Immunol 1997; 159: 5661–5670. Blood 1991; 78: 1448–1451. 22 Nandurkar HH, Robb L, Nicholl JK, Hilton DJ, Sutherland GR, 41 Tsuji K, Lyman SD, Sudo T, Clark SC, Ogawa M. Enhancement Begley CG. The gene for the human interleukin-11 receptor alpha of murine hematopoiesis by synergistic interactions between steel chain locus is highly homologous to the murine gene and contains factor (ligand for c-kit), interleukin-11, and other early acting fac- alternatively spliced first exons. Int J Biochem Cell Biol 1997; 29: tors in culture. Blood 1992; 79: 2855–2860. 753–766. 42 Weich NS, Wang A, Fitzgerald M, Neben TY, Donaldson D, Gian- 23 Cherel M, Sorel M, Apiou F, Lebeau B, Dubois S, Jacques Y, Min- notti J, Yetz-Aldape J, Leven RM, Turner KJ. Recombinant human vielle S. The human interleukin-11 receptor alpha gene (IL11RA): interleukin-11 directly promotes megakaryocytopoiesis in vitro. genomic organization and chromosome mapping. Genomics Blood 1997; 90: 3893–3902. 1996; 32: 49–53. 43 Quesniaux VFJ, Clark SC, Turner K, Fagg B. Interleukin-11 stimu- 24 Cherel M, Sorel M, Lebeau B, Dubois S, Moreau JF, Bataille R, lates multiple phases of erythropoiesis in vitro. Blood 1992; 80: Minvielle S, Jacques Y. Molecular cloning of two isoforms of a 1218–1223. receptor for the human hematopoietic cytokine interleukin-11. 44 Yin T, Schendel P, Yang Y-C. Enhancement of in vitro and in vivo Blood 1995; 86: 2534–2540. antigen-specific antibody responses by interleukin-11. J Exp Med 25 Robb L, Hilton D, Willson T, Begley C. Structural analysis of the 1992; 175: 211–216. gene encoding the murine interleukin-11 receptor alpha chain and 45 Schlerman FJ, Bree AG, Kaviani M, Nagle SL, Donnelly LH, Mason alpha related locus. J Biol Chem 1996; 271: 13754–13761. LE, Schaub RG, Grupp SA, Goldman SJ. Thrombopoietic activity 26 Neddermann P, Graziani R, Ciliberto G, Paonessa G. Functional of recombinant human interleukin-11 (rhIL-11) in normal and expression of soluble human interleukin-11 (IL-11) receptor alpha myelosuppressed nonhuman primates. Stem Cells 1996; 14: and stoichiometry of in vitro IL-11 receptor complexes with 517–532. gp130. J Biol Chem 1996; 271: 30986–30991. 46 Bree A, Schlerman F, Timony G, McCarthy K, Stoudemire J. Phar- 27 Nandurkar HH, Hilton DJ, Nathan P, Willson T, Nicola N, Begley macokinetics and thrombopoietic effects of recombinant human CG. The human IL-11 receptor requires gp130 for signalling: dem- interleukin-11 (rhIL-11) in nonhuman primates and rodents. Blood onstration by molecular cloning of the receptor. Oncogene 1996; 1991; 78 (Suppl. 1): 132a (Abstr.). 12: 585–593. 47 Neben TY, Loebelenz J, Hayes L, McCarthy K, Stoudemire J, 28 Nandurkar HH, Robb L, Tarlinton D, Barnett L, Kontgen F, Begley Schaub R, Goldman SJ. Recombinant human interleukin-11 stimu- CG. Adult mice with targeted mutation of the interleukin-11 lates megakaryocytopoiesis and increases peripheral platelets in receptor (IL11Ra) display normal hematopoiesis. Blood 1997; 90: normal and splenectomized mice. Blood 1993; 81: 901–908. 2148–2159. 48 Goldman SJ. Preclinical biology of interleukin 11: a multifunc- 29 Bilinski P, Roopenian D, Gossler A. Maternal IL-11R␣ function is tional hematopoietic cytokine with potent thrombopoietic activity. required for normal decidua and fetoplacental development in Stem Cells 1995; 13: 462–471. mice. Genes Dev 1998; 12: 2234–2243. 49 Leonard JP, Quinto CM, Kozitza MK, Neben TY, Goldman SJ. 30 Robb L, Li R, Hartley L, Nandurkar HH, Koentgen F, Begley CG. Recombinant human interleukin-11 stimulates multilineage hema- Infertility in female mice lacking the receptor for interleukin 11 is topoietic recovery in mice after a myelosuppressive regimen of due to a defective uterine response to implantation. Nature Med sublethal irradiation and carboplatin. Blood 1994; 83: 1499– 1998; 4: 303–308. 1506. 31 Elias JA, Zheng T, Einarsson O, Landry M, Trow T, Rebert N, Panu- 50 Hitz SL, Kaviani MD, Schlerman FJ, Bree AG, Grupp SA, Goldman ska J. Epithelial interleukin-11: regulation by cytokines, respiratory SJ. The hematologic effects of recombinant human interleukin 11 syncytial virus, and retinoic acid. J Biol Chem 1994; 269: in a myelosuppressed nonhuman primate model. Blood 1995; 86 22261–22268. (Suppl. 1): 898a (Abstr.). 32 Einarsson O, Geba P, Zhu Z, Landry M, Elias JA. Interleukin-11: 51 Gordon MS, McCaskill-Stevens WJ, Battiato LA, Loewy J, Loesch stimulation in vivo and in vitro by respiratory viruses and induc- D, Breeden E, Hoffman R, Beach KJ, Kuca B, Kaye J, Sledge GW. tion of airways hyperresponsiveness. J Clin Invest 1996; 97: A phase I trial of recombinant human interleukin-11 (Neumega 915–924. rhIL-11 growth factor) in women with breast cancer receiving 33 Elias JA, Zheng T, Whiting NL, Trow TK, Merrill WW, Zitnik R, chemotherapy. Blood 1996; 87: 3615–3624. Ray P, Alderman EM. IL-1 and transforming growth factor-␤ regu- 52 Tepler I, Elias L, Smith JW II, Hussein M, Rosen G, Chang AY-C, lation of fibroblast-derived IL-11. J Immunol 1994; 152: 2421– Moore JO, Gordon MS, Kuca B, Beach KJ, Loewy JW, Garnick 2429. MB, Kaye JA. A randomized placebo-controlled trial of recombi- 34 Zheng T, Nathanson MH, Elias JA. Histamine augments cytokine- nant human interleukin-11 in cancer patients with severe throm- stimulated IL-11 production by human lung fibroblasts. J Immunol bocytopenia due to chemotherapy. Blood 1996; 87: 3607–3614. 1994; 153: 4742–4752. 53 Schwerkoske J, Schwartzberg L, Weaver CH, Schwertschlag US, 35 Maier R, Ganu V, Lotz M. Interleukin-11, an inducible cytokine Goodfellow J, Bedrosian CL. Phase 1 rhIL-11 auto-BMT Mucositis in human articular chondrocytes and synoviocytes, stimulates the Group. A phase 1 double-masked, placebo-controlled study to Review US Schwertschlag et al 1314 evaluate tolerability of Neumega (rhil-11; oprelvekin) to reduce of interleukin-11-mediated bone resorption by cyclooxygenases mucositis in patients with solid tumors or lymphoma receiving inhibitors. J Cell Physiol 1998; 175: 247–254. high-dose chemotherapy (ct) with autologous peripheral blood 73 Verhaeghe J, Van Herck E, Van Bree R, Bouillon R, Dequeker J, stem cell reinfusion. Proc Am Soc Clin Oncol 1999; 18: 584a Keith JC Jr. Recombinant human interleukin-11 does not modify (Abstr.). biochemical parameters of bone remodeling and bone mineral 54 Dykstra KH, Loewy J, Schwertschlag U, Kaye JA. A mathematical density in adult ovariectomized rats. J Interfer Cytok Res 1998; model of the kinetics of platelet production after high-dose 18: 49–53. chemotherapy and treatment with Neumega (rhIL-11). Blood 74 Taki H, Sugiyama E, Mino T, Kuroda A, Kobayashi M. Differential 1997; 90: 184b. inhibitory effects of indomethacin, dexamethasone, and inter- 55 Booth C, Potten CS. Effects of IL-11 on the growth of intestinal feron-gamma (IFN-␥) on IL-11 production by rheumatoid synovial epithelial cells in vitro. Cell Prolif 1995; 28: 581–594. cells. Clin Exp Immunol 1998; 112: 133–138. 56 Peterson RL, Bozza MM, Dorner AJ. Interleukin-11 induces intesti- 75 Hermann JA, Hall MA, Maini RN, Feldmann M, Brennan FM. nal epithelial cell growth arrest through effects on retinoblastoma Important immunoregulatory role of interleukin-11 in the protein phosphorylation. Am J Pathol 1996; 149: 895–902. inflammatory process in rheumatoid arthritis. Arthritis Rheum 57 Du XX, Doerschuk CM, Orazi A, Williams DA. A bone marrow 1998; 41: 1388–1397. stromal-derived growth factor, interleukin-11, stimulates recovery 76 Trepicchio WL, Bozza M, Pedneault G, Dorner AJ. Recombinant of small intestinal mucosal cells after cytoablative therapy. Blood human IL-11 attenuates the inflammatory response through down- 1994; 83: 33–37. regulation of proinflammatory cytokine release and nitric oxide 58 Orazi A, Du Z, Yang Z, Kashai M, Williams DA. Interleukin-11 production. J Immunol 1996; 157: 3627–3634. prevents apoptosis and accelerates recovery of small intestinal 77 Redlich CA, Gao X, Rockwell S, Kelley M, Elias JA. IL-11 enhances mucosa in mice treated with combined chemotherapy and radi- survival and decreases TNF production after radiation-induced ation. Lab Invest 1996; 75: 33–42. thoracic injury. J Immunol 1996; 157: 1705–1710. 59 Sonis S, Muska A, O’Brien J, Van Vugt A, Langer-Safer P, Keith J. 78 Leng SX, Elias JA. Interleukin-11 inhibits macrophage interleukin- Alteration in the frequency, severity and duration of chemo- 12 production. J Immunol 1997; 159: 2161–2168. therapy-induced mucositis in hamsters by interleukin-11. Eur J 79 Du XX, Neben T, Goldman S, Williams DA. Effects of recombinant Cancer B Oral Oncol 1995; 31b: 261–266. human interleukin-11 on hematopoietic reconstitution in trans- 60 Sonis ST, Van Vugt AG, McDonald J, Dotoli E, Schwertschlag U, plant mice: acceleration of recovery of peripheral blood neutro- Szklut P, Keith J. Mitigating effects of interleukin 11 on consecu- phils and platelets. Blood 1993; 81: 27–34. tive courses of 5-fluorouracil-induced ulcerative mucositis in ham- 80 Bozza M, Kyvelos D, Trepicchio WL, Collins M, Klempner MS, sters. Cytokine 1997; 9: 605–612. Dorner AJ. Recombinant human interleukin-11 does not affect 61 Du X, Liu Q, Yang Z, Orazi A, Rescorla FJ, Grosfeld JL, Williams functions of purified human neutrophils in vitro. J Interf Cytok Res DA. Protective effects of interleukin-11 in a murine model of isch- 1998; 18: 889–895. emic bowel necrosis. Am J Physiol 1997; 272: 545–552. 81 Neben S, Donaldson D, Fitz L, Calvetti J, Neben T, Turner K, 62 Fiore NF, Ledniczky G, Liu Q, Orazi A, Du X, Williams DA, Gros- Hirayama F, Ogawa M. Interleukin-4 (IL-4) in combination with feld JL. Comparison of interleukin-11 and epidermal growth factor IL-11 or IL-6 reverses the inhibitory effect of IL-3 on early B lym- on residual small intestine after massive small bowel resection. J phocyte development. Exp Hematol 1996; 24: 783–789. Pediatr Surg 1998; 33: 24–29. 82 Anderson KC, Morimoto C, Paul SR, Chauhan D, Williams D, 63 Liu Q, Du XX, Schindel DT, Yang ZX, Rescorla FJ, Williams DA, Cochran M, Barut BA. Interleukin-11 promotes accessory cell- Grosfeld JL, Smith S, Hendren WH, Guzzetta PC, Bruch SW. dependent B-cell differentiation in humans. Blood 1992; 80: Trophic effects of interleukin-11 in rats with experimental short 2797–2804. bowel syndrome. J Pediatr Surg 1996; 31: 1047–1051. 83 Keith JC Jr, Albert L, Sonis ST, Pfeiffer CJ, Schaub RG. IL-11, a pleiotropic cytokine: exciting new effects of IL-11 on gastrointes- 64 Baumann H, Schendel P. Interleukin-11 regulates the hepatic tinal mucosal biology. Stem Cells (Dayt) 1994; 12 (Suppl. 1): expression of the same plasma protein genes as interleukin-6. J 79–90. Biol Chem 1991; 266: 20424–20427. 84 Peterson RL, Wang L, Albert L, Keith JC Jr, Doner AJ. Molecular 65 Roeb E, Graeve L, Hoffman R, Decker K, Edwards DR, Heinrich effects of recombinant human interleukin-11 in the HLA-B27 rat PC. Regulation of tissue inhibitor of metalloproteinases-1 gene model of inflammatory bowel disease. Lab Invest 1998; 78: expression by cytokines and dexamethasone in rat hepatocyte pri- 1503–1512. mary cultures. Hepatology 1993; 18: 1437–1442. 85 Albert LM, Ferranti TJ, Erickson JE, Donnelly LH, Schaub RG, Keith 66 Fukuda Y, Sassa S. Effect of interleukin-11 on the levels of mRNAs JC Jr. Dose response and schedule studies of recombinant human encoding heme oxygenase and haptoglobin in human HEPG2 interleukin-11 in acetic acid-induced colonic injury in rats. Gas- hepatoma cells. Biochem Biophys Res Commun 1993; 193: troenterology 1995; 108 (Suppl. 4): A768 (Abstr.). 297–302. 86 Qiu BS, Pfeiffer CJ, Keith JC Jr. Protection by recombinant human 67 Kaye JA, Loewy J, Blume J, Clendaniel A, Egan A, Garnick MB, interleukin-11 against experimental TNBS-induced colitis in rats. Mitchell J, Knowles C, Ault KA. Recombinant human interleukin Dig Dis Sci 1996; 41: 1625–1630. eleven (NEUMEGA rhIL-11 growth factor) increases plasma von 87 Pfeiffer CJ, Sato S, Qiu BS, Keith JC Jr, Ta SE. Cellular pathology Willebrand factor and fibrinogen concentrations in normal human of experimental colitis induced by trinitrobenzenesulphonic acid subjects. Blood 1994; 84 (Suppl. 1): 276a (Abstr.). (TNBS): protective effects of. Inflammopharmacology 1997; 5: 68 Kawashima I, Ohsumi J, Mita-Honjo K, Shimoda-Takano K, Ishi- 363–381. kawa H, Sakakibara S, Miyadai K, Takiguchi Y. Molecular cloning 88 Waxman AB, Einarsson O, Seres T, Knickelbein RG, Warshaw JB, of cDNA encoding adipogenesis inhibitory factor and identity with Johnston R, Homer RJ, Elias JA. Targeted lung expression of interleukin-11. Fed Eur Biochem Soc Lett 1991; 283: 199–202. interleukin-11 enhances murine tolerance of 100% oxygen and 69 Ohsumi J, Miyadai K, Kawashima I, Ishikawa-Ohsumi H, Sakakib- diminishes hyperoxia-induced DNA fragmentation. J Clin Invest ara S, Mita-Honjo K, Takiguchi Y. Adipogenesis inhibitory factor: 1998; 101: 1970–1982. a novel inhibitory regulator of adipose conversion in bone mar- 89 Hill GR, Cooke KR, Teshmia T, Crawford JM, Keith JC Jr, Brinson row. Fed Eur Biochem Soc Lett 1991; 288: 13–16. YS, Bungard D, Ferrara JLM. Interleukin-11 promotes T cell polar- 70 Fuhrer DK, Yang YC. Activation of Src-family protein tyrosine kin- ization and prevents acute graft-versus-host disease after allog- ases and phosphatidylinositol 3-kinase in 3T3-L1 mouse preadipo- eneic bone marrow transplantation. J Clin Invest 1998; 102: cytes by. Exp Hematol 1996; 24: 195–203. 115–123. 71 Passeri G, Girasole G, Knutson S, Yang Y-C, Manolagas SC, Jilka 90 Barton BE, Shortall J, Jackson JV. Interleukins 6 and 11 protect RL. Interleukin-11 (IL-11): a new cytokine with osteoclastogenic mice from mortality in a staphylococcal enterotoxin-induced toxic and bone resorptive properties and a critical role in PTH- and shock model. Infect Immun 1996; 64: 714–718. 1,25(OH)2D3-induced osteoclast development. J Bone Min Res 91 Misra BR, Ferranti TJ, Keith JC Jr, Donnelly LH, Erickson JE, Schaub 1993; 7 (Suppl. 1): S110 (Abstr.). RG. Recombinant human interleukin-11 prevents hypotension in 72 Morinaga Y, Fujita N, Ohishi K, Zhang YK, Tsuruo T. Suppression LPS-treated anesthetized rabbits. J Endotox Res 1996; 3: 297–305. Review US Schwertschlag et al 1315 92 Opal SM, Jhung JW, Keith JC, Palardy JE, Parejo NA, Young LD, 96 Dykstra K, Rogge H, Stone A, Loewy J, Schwertschlag U. Effect of Bhattacharjee A. Recombinant human interleukin-11 in experi- diuretic treatment on rhIL-11-induced salt and water retention. mental pseudomonas aeruginosa sepsis in immunocompromised Blood 1996; 88: 346a (Abstr.). animals. J Infect Dis 1998; 178: 1205–1208. 97 Ault KA, Mitchell J, Knowles C, Clendaniel A, Egan A, Loewy J, 93 Takagi A, Yabe Y, Oka Y, Sawai K, Takakura Y, Hashida M. Renal Garnick MB, Kaye JA. Recombinant human interleukin eleven disposition of recombinant human interleukin-11 in the isolated (Neumega rhIL-11 growth factor) increases plasma volume and perfused rat kidney. Pharm Res 1997; 14: 86–90. decreases urine sodium excretion in normal human subjects. 94 Aoyama K, Uchida T, Takanuki F, Usui T, Watanabe T, Higuchi S, Blood 1994; 84: (Suppl. 1): 276a (Abstr.). Toyoki T, Mizoguchi H. Pharmacokinetics of recombinant human 98 Sands B, Bank S, Sninsky C, Robinson M, Katz S, Singleton J, interleukin-11 (rhIL-11) in healthy male subjects. Br J Clin Pharma- Miner P, Safdi M, Galandiuk S, Hanauer S, Varilek G, Buchman col 1997; 43: 571–578. A, Rogers V, Salzberg B, Cai B, Rogge H, Schwertschlag U. Safety 95 Hutabarat R, Dykstra K, Patterson F, Sica D, Schwertschlag U. and activity evaluation of rhIL-11 in subjects with active Crohn’s Pharmacokinetic study of rhIL-11 in subjects with renal failure and disease. Gastroenterology 1999; 117: 1–8. normal volunteers. Pharm Res 1997; 14: S606.