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Cells in Vivo and in Vitro II on Expression of CXCL5 by Alveolar IL-17A and TNF-α Exert Synergistic Effects on Expression of CXCL5 by Alveolar Type II Cells In Vivo and In Vitro This information is current as Yuhong Liu, Junjie Mei, Linda Gonzales, Guang Yang, Ning of September 29, 2021. Dai, Ping Wang, Peggy Zhang, Michael Favara, Kenneth C. Malcolm, Susan Guttentag and G. Scott Worthen J Immunol published online 31 January 2011 http://www.jimmunol.org/content/early/2011/01/31/jimmun ol.1002016 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 31, 2011, doi:10.4049/jimmunol.1002016 The Journal of Immunology IL-17A and TNF-a Exert Synergistic Effects on Expression of CXCL5 by Alveolar Type II Cells In Vivo and In Vitro Yuhong Liu,*,1 Junjie Mei,*,1 Linda Gonzales,*,1 Guang Yang,* Ning Dai,* Ping Wang,* Peggy Zhang,* Michael Favara,* Kenneth C. Malcolm,† Susan Guttentag,*,‡ and G. Scott Worthen*,‡ CXCL5, a member of the CXC family of chemokines, contributes to neutrophil recruitment during lung inflammation, but its regulation is poorly understood. Because the T cell-derived cytokine IL-17A enhances host defense by triggering production of chemokines, particularly in combination with TNF-a, we hypothesized that IL-17A would enhance TNF-a–induced expression of CXCL5. Intratracheal coadministration of IL-17A and TNF-a in mice induced production of CXCL1, CXCL2, and CXCL5, which was associated with increased neutrophil influx in the lung at 8 and 24 h. The synergistic effects of TNF-a and IL17A were greatly attenuated in Cxcl52/2 mice at 24 h, but not 8 h, after exposure, a time when CXCL5 expression was at its peak in wild- Downloaded from type mice. Bone marrow chimeras produced using Cxcl52/2 donors and recipients demonstrated that lung-resident cells were the source of CXCL5. Using differentiated alveolar epithelial type II (ATII) cells derived from human fetal lung, we found that IL-17A enhanced TNF-a–induced CXCL5 transcription and stabilized TNF-a–induced CXCL5 transcripts. Whereas expression of CXCL5 required activation of NF-kB, IL-17A did not increase TNF-a–induced NF-kB activation. Apical costimulation of IL- 17A and TNF-a provoked apical secretion of CXCL5 by human ATII cells in a transwell system, whereas basolateral costimu- lation led to both apical and basolateral secretion of CXCL5. The observation that human ATII cells secrete CXCL5 in a polarized http://www.jimmunol.org/ fashion may represent a mechanism to recruit neutrophils in host defense in a fashion that discriminates the site of initial injury. The Journal of Immunology, 2011, 186: 000–000. ung host defense requires both innate and adaptive im- signals in induction of ATII cell responses, and which cytokines mune responses acting in a highly coordinated manner. and chemokines are released, remains unclear. L Innate responses are initiated by microbial recognition via In addition to innate responses, adaptive immune responses, pattern recognition receptors. This recognition triggers the acti- characterized by specificity and memory and mediated primarily by vation of transcription factors, release of early response cytokines T and B lymphocytes, are important in host defense (11, 12). by guest on September 29, 2021 (particularly TNF-a) (1–3) and chemokines, recruitment of neu- Recent evidence suggests that a specific subset of CD4+ T cells trophils, and consequent clearance of microorganisms (4–6). Al- secreting IL-17 plays a nonredundant role in directing innate though alveolar macrophages (AMs) have been accepted as an responses (12). IL-17A is the prototype member of IL-17 family, important component of innate immunity in the lung, alveolar type which is associated with increased neutrophil influx through in- II (ATII) cells have recently been demonstrated to be an active duction of proinflammatory cytokines and chemokines during participant in the innate immune response. ATII cells participate bacterial infection (13–16). Which lung cell responds to IL-17A, in lung host defense not only by secreting surfactant lipids (7) and however, and the signals released that promote neutrophil accu- surfactant-associated proteins (8) to block and opsonize bacteria mulation is not known. The best-known candidates, however, are and virus, but also by releasing chemokines to facilitate movement glutamic acid-leucine-arginine (ELR)+ CXC chemokines. of immune cells (9, 10). Despite these insights, the role of specific CXCL5 (known as LPS-induced CXC chemokine [LIX] in mice and epithelial cell-derived neutrophil-activating peptide-78 [ENA- 78] in human) is a unique member of ELR+ CXC family of chemokines, which are responsible for mediating neutrophil re- *Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA cruitment into tissues during inflammation and infection (17). 19014; †Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206; and ‡University of Pennsylvania, Philadelphia, PA 19014 ENA-78 has been found to be involved in a variety of human 1Y.L., J.M., and L.G. contributed equally to this work. inflammatory diseases (18–27), such as chronic obstructive pul- monary disease, exacerbation of asthma and chronic obstructive Received for publication June 29, 2010. Accepted for publication December 23, 2010. pulmonary disease, acute coronary syndromes, diabetes mellitus, This work was supported by National Institutes of Health Grant HL068876. and inflammatory bowel diseases. Murine Cxcl5 was first cloned Address correspondence and reprint requests to Dr. G. Scott Worthen, Division of as a LPS response gene that could be attenuated by glucocorti- Neonatology, Abramson Research Center, Room #414C, Children’s Hospital of Phil- coids (28). In comparison with other CXC chemokines, specifi- adelphia, Philadelphia, PA19014. E-mail address: [email protected] cally CXCL1 (also referred to as keratinocyte chemoattractant Abbreviations used in this article: AM, alveolar macrophage; ATII, alveolar type II [KC]) and CXCL2 (also referred to as MIP-2), CXCL5 was shown cell; BALF, bronchoalveolar lavage fluid; BM, bone marrow; CHX, cycloheximide; DCI, dexamethasone plus 8-Br-cAMP plus isobutylmethylxanthine; ELR, glutamic to have distinct induction kinetics, tissue distribution, and sensi- acid-leucine-arginine; ENA-78, epithelial cell-derived neutrophil-activating peptide- tivity to glucocorticoids in an acute endotoxemia model (29). We 78; i.t., intratracheal; KC, keratinocyte chemoattractant; LIX, LPS-induced CXC have previously shown (10) that CXCL5 was expressed by ATII chemokine; qPCR, quantitative PCR; rm, recombinant mouse; WT, wild-type. cells through immunohistochemical analysis and primary rodent Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 ATII cell culture, in response to LPS stimulation, whereas KC and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002016 2 SYNERGISTIC EFFECTS OF IL-17A AND TNF-a ON CXCL5 EXPRESSION MIP-2 are mainly expressed by alveolar macrophages. We further xylazene (10 mg/kg), and a midventral incision was performed. After generated Cxcl5-deficient mice and demonstrated the nonre- isolation of muscles, the trachea was exposed, and each mouse was in- 6 7 m dundant but opposing roles of CXCL5 in mediating neutrophil oculated with 10 or 10 CFU E. coli in 50 l in 0.9% saline. The mice were humanely sacrificed at 8 and 24 h postinfection, and BALF was col- influx to the lung in a localized LPS inhalation model and a severe lected. Escherichia coli pneumonia model (30). Upon LPS inhalation, CXCL5 expression in bronchoalveolar lavage fluid (BALF) was Intratracheal administration of recombinant mouse IL-17A a much more persistent than KC and MIP-2, which contributed to its and/or recombinant mouse TNF- dominant role in mediating neutrophil influx to the lung. Fur- C57BL/6 mice were divided into four groups as follows: 1) PBS alone; 2) thermore, in a model of severe E. coli pneumonia, CXCL5 release recombinant mouse (rm)IL-17A (625 ng/mouse) alone; 3) rmTNF-a (500 induced high levels of KC and MIP-2 in both BALF and plasma ng/mouse) alone; and 4) rmIL-17A plus rmTNF-a. All treatments were administered in a volume of 50 ml. Mice were euthanized at 4, 8, and 24 h. at least partially through inhibiting chemokine scavenging and 2/2 Cxcl5 mice were compared with C57BL/6 mice receiving rmIL-17A thereby modifying the inflammatory response. Although our group plus rmTNF-a at 8 and 24 h. has described CXCL5 as a product of ATII cells in mice and rats, and as a critical player in lung inflammation and pulmonary host Generation of chimeric mice by bone marrow reconstitution defense, whether human ATII cells respond similarly is unknown. The 6–8-wk-old recipient mice were lethally irradiated in two doses of 800 Furthermore, the stimuli that induce CXCL5 in the ATII cell are and 400 rad with an interval of 3 h. Bone marrow (BM) from donor mice poorly characterized. Because previous reports have indicated that was harvested from both the tibiae and femora. After lysis of red cells, ∼5 IL-17A in combination with TNF-a increased synergistically the million cells were i.v. injected into recipient mice after lethal irradiation.
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