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Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-Versus-Host Disease M

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Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-Versus-Host Disease M Overexpression of Tissue Inhibitor of Metalloproteinases-3 in Intestinal and Cutaneous Lesions of Graft-versus-Host Disease M. T. Salmela, M.D., M. L. Karjalainen-Lindsberg, M.D., Ph.D., L. Jeskanen, M.D., U. Saarialho-Kere, M.D., Ph.D. Departments of Dermatology (MTS, LJ, US-K) and Pathology (MLK-L), Helsinki University Central Hospital, Helsinki, Finland cells in 12/13 and 10/13 gut samples, respectively. Matrix metalloproteinases (MMPs) have been impli- Whereas TIMP-1 was expressed particularly by sub- cated in the pathobiology of various T-cell–medi- epithelial cells where epithelium had shed away, ated inflammatory disorders of the intestine and TIMP-3 was detected in deeper areas. We conclude skin. Their synthetic inhibitor has been shown to that MMPs are differentially regulated in the skin prevent lethal acute graft-versus-host disease in an- and gut lesions of graft-versus-host disease. In imal models. We intended to determine the expres- agreement with previous data on cancer cells, sion of MMPs 1, 3, 7, 9, 10, 12, and 19 and tissue TIMP-3, induced by TGF-␤1, may contribute to the inhibitors of metalloproteinases (TIMPs) 1 and 3 in apoptosis of keratinocytes in cutaneous graft- intestinal and cutaneous lesions of patients suffer- versus-host disease lesions, leading to typical his- ing from graft-versus-host disease after bone mar- topathological changes. We also conclude that row transplantation. In situ hybridizations for MMPs play a less important role as effector mole- MMPs 1, 3, 7, 10, and 12 as well as TIMPs 1 and 3 35 cules in intestinal graft-versus-host disease than in were performed using S-labeled cRNA probes on celiac or inflammatory bowel disease. (9 ؍ and cutaneous specimens (n (13 ؍ intestinal (n from patients with graft-versus-host disease. Immu- KEY WORDS: Apoptosis, Collagenase, Matrilysin, nohistochemical stainings were carried out to local- ␤ MMP-19, TIMP. ize MMP-9, MMP-19, TIMP-3, and TGF- 1 proteins, Mod Pathol 2003;16(2):108–114 and TUNEL staining, to detect apoptotic cells. TIMP-3 mRNA and protein were detected in cuta- Graft-versus-host disease is the major cause of mor- neous lesions in areas with vacuolar degeneration bidity and mortality after bone marrow transplan- of the basal epidermal layer in all skin samples, and tation and is sometimes, though more rarely, they colocalized with apoptotic keratinocytes and threatening patients after liver transplantation (1, partly with staining for TGF-␤. None of the MMPs 2). In graft-versus-host disease, immunocompetent examined were overexpressed in skin lesions. Sig- donor lymphocytes from transplanted bone mar- nals for MMP-1 and MMP-3 mRNA was found in row or liver recognize and react against recipient’s 10/13 and 5/13 intestinal biopsies, respectively. In tissues, leading to cutaneous and intestinal lesions. the gut, MMP-19–positive epithelial cells, particu- Commonly, the first manifestation of acute graft- larly in the crypts, were found in 10/13 samples. versus-host disease is pruritic maculopapular skin Expression of MMPs 7, 9, 10, and 12 was absent or very low. TIMPs 1 and 3 were expressed by stromal rash characterized by typical histopathological findings such as vacuolar degeneration of the basal cell layer, basal cell necrosis, Langerhans cell de- Copyright © 2003 by The United States and Canadian Academy of pletion, intercellular edema, and acantholysis (1, 2). Pathology, Inc. VOL. 16, NO. 2, P. 108, 2003 Printed in the U.S.A. Intestinal manifestations of acute graft-versus-host Date of acceptance: November 11, 2002. disease include diarrhea, abdominal cramping, in- Supported by The Academy of Finland, the Sigrid Juselius Foundation, Finska Läkaresällskapet, Helsinki University Central Hospital Research testinal bleeding, and vomiting. Endoscopic find- Funds, Biomedicum Foundation, Emil Aaltonen Foundation, and Re- ings range from normal to extensive edema, muco- search and Science Foundation of Farmos. Address reprint requests to: U. Saarialho-Kere, M.D., Ph.D., Depart- sal sloughing and bleeding, and histology reveals, ment of Dermatology, Helsinki University Central Hospital, Meilah- for example, crypt-cell necrosis (1, 2). dentie 2, 00250 Helsinki, Finland; fax: ϩ358-9-4718 6561; e-mail: [email protected]. Matrix metalloproteinases (MMPs) are a family of 2ϩ DOI: 10.1097/01.MP.0000051681.43441.82 Ca -dependent zinc-ion containing endopepti- 108 dases. Since the early sixties, 21 human members of marrow transplantation (19, 20). TNF-␣ and FasL, this enzyme family have been cloned. According to both released and activated by MMPs (3, 21), are their structure and substrate specificity, MMPs can implicated in the pathogenesis of acute graft- be grouped into collagenases (MMP-1, -8, and 13), versus-host disease (22). In addition to the effects of gelatinases (MMP-2 and -9), stromelysins (MMP-3, MMPs on the activation of cytokines or on the -10, -11, and -12), membrane-type metalloprotein- shedding of their receptors (23), they might func- ases (MMP-14, -15, -16, -17, and -24), matrilysins tion as end-stage effector molecules in intestinal (MMP-7 and -26), and other MMPs (MMP-19, -20, and cutaneous lesions also in graft-versus-host dis- -23, -25, and -28; 3, 4). MMPs are regulated mainly ease. Therefore, we wanted to investigate whether at the transcriptional level, and their enzymatic ac- MMPs 1, 3, 7, 9, 10, 12, and 19 and TIMPs 1 and 3 tivity can be inhibited by tissue inhibitors of met- are expressed in graft-versus-host disease–related alloproteinases (TIMP), a protein group that cur- lesions of the skin and intestine. Our results indi- rently comprises four members (TIMP-1, -2, -3, and cate that TIMP-3 might contribute to basal cell ap- -4). TIMP-1 inhibits the activity of most MMPs ex- optosis in cutaneous lesions, whereas none of the cept MMP-2 and MT1-MMP (5, 6). TIMP-3 inhibits MMPs was overexpressed. In contrast, expression the activity of MMPs -1, -2, -3, -9, and -13 (7). In of MMPs-1, and -19 and TIMPs 1 and 3 was ob- addition, it inhibits the endopeptidase TACE served in intestinal graft-versus-host lesions. (ADAM-17) (8), which can shed TNFR1 and TNF-␣ from the cell surface. MMPs play an important role in several physiological and pathological processes MATERIALS AND METHODS such as fetal development; wound healing; inflam- matory bowel disease; rheumatoid arthritis; and Samples cancer growth, invasion, and metastasis (3). Formalin-fixed, paraffin-embedded specimens of Matrix metalloproteinases and TIMPs have previ- intestine (n ϭ 13) and skin (n ϭ 9) from 16 patients ously been implicated in the pathomechanism of sev- were obtained from the Department of Pathology, eral inflammatory disorders of the skin and intestine, Helsinki University Central Hospital. Intestinal and such as celiac disease, ulcerative colitis, and Crohn’s skin specimens were from different patients. Fif- disease (9, 10), as well as granulomatous skin disor- teen patients had undergone bone marrow trans- ders, lichen planus, and scleroderma (11–14). Several plantation and one patient, liver transplantation. studies have shown the expression of various MMPs, Each sample was investigated by an experienced particularly MMPs -1, -3, -12 and -14, in intestinal pathologist, and the diagnosis of cutaneous graft- ulcers of patients with inflammatory bowel disease (9, versus-host disease was verified by a dermato- 10, 15, 16). Functional evidence for the critical role of pathologist. Cutaneous and intestinal samples were MMPs, particularly that of MMP-3, in mucosal injury graded (Tables 1 and 2) according to previously comes from studies using a fetal model for T-cell– published criteria (24, 25). mediated injury of the gut (17, 18). In this model, the synthetic MMP inhibitor prevents mucosal injury af- ter T cell activation. In Situ Hybridization The synthetic MMP inhibitor (KB-R7785), with The production and specificity of the anti-sense activity against MMPs-1, -3, and -9, prevents acute human MMP-1, -3, -7, -10, and -12 and TIMPs-1 graft-versus-host disease but preserves graft-versus- and -3 cRNA probes have been described (10, 26– leukemia effect in mice undergoing allogeneic bone 29). After treatment with proteinase K, 4-␮m sec- TABLE 1. Clinicopathological Information and In Situ Hybridization or Immunohistochemistry Results for Patients with Cutaneous GVHD after Bone Marrow Transplantation Patient Sex Age Grade Time from Transplantation MMP-1 MMP-3 TIMP-1 TIMP-3 HME S2 M Ϫ92 Ϫ19 1 F 30 III 2 mo AML ϪϪsϩ eϩ eϩϩ etϩ sϩϪϪSGϩϪ Ϫ 2 M 45 III 4 mo PBC* ϪϪsϩϩϩ eϩϩϩ etϩ sϩϩ Ϫ Ϫ SGϩ (ϩ)etϩ 3 F 52 III 1 mo CML ϪϪsϩϩ eϩϩϩ etϩ sϩϪϪSGϩϪ et ϩ 4 M 46 II 6 mo AML ϪϪϪeϩϩϩ etϩ s(ϩ) ϪϪSGϩϪ Ϫ 5 M 17 Early st of late 6 mo ALL ϪϪeϩ eϩ sϪϪϪϪϪϪ I 6 mo ALL ϪϪϪeϩϩϩ etϩ sϩϪϪSGϩϪet (ϩ) 6 M 11 Late st of late 19 mo AA ϪϪs(ϩ)eϩϩϩ etϩ sϩϩ Ϫ Ϫ SGϩϪ Ϫ 7 M 51 III 7 mo CLL Ϫ N.D. N.D. N.D. ϪϪN.D. ϪϪ 8 M 52 II 2 mo CLL Ϫ N.D. N.D. N.D. ϪϪN.D. Ϫ et (ϩ) e ϭ epithelium; s ϭ stroma; et ϭ endothelium; SG ϭ sweat gland; N.D. ϭ not determined; PBC ϭ primary biliary cirrhosis; CML ϭ chronic myeloid leukaemia; AA ϭ aplastic anemia; AML ϭ acute myeloid leukaemia; ALL ϭ acute lymphocytic leukemia; CLL ϭ chronic lymphocytic leukemia. * Liver transplantation. ϩϩϩ ϭ specific signal in large number of cells; ϩϩ ϭ specific signal in moderate number of cells; ϩϭspecific signal in low number of cells; (ϩ) ϭ specific signal in occasional cells; Ϫϭno specific signal detected. Matrix Metalloproteinases in Graft-versus-Host Disease (M.T.
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