Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
11 April 2017
In the version of this article initially published, there were two typographical errors in the Abstract. The unnecessary ‘h’ in the line “Furthermore, h according to…..” has been deleted. The line “OSM is thus a potential biomarker of and therapeutic target for IBD,….” was changed to read “OSM is thus a potential biomarker and therapeutic target for IBD…”. These errors have been corrected in the HTML and PDF versions of the article. A coding error that inadvertently resulted in incorrect ordering of the authors in the HTML version was also corrected.
References
Uniken Venema, W.T., Voskuil, M.D., Dijkstra, G., Weersma, R.K. & Festen, E.A. The genetic background of inflammatory bowel disease: from correlation to causality. J. Pathol. 241, 146–158 (2017).
Basson, A., Trotter, A., Rodriguez-Palacios, A. & Cominelli, F. Mucosal interactions between genetics, diet, and microbiome in inflammatory bowel disease. Front. Immunol. 7, 290 (2016).
de Souza, H.S.P. & Fiocchi, C. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 13, 13–27 (2016).
Maloy, K.J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).
Neurath, M.F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 14, 329–342 (2014).
Chen, M.L. & Sundrud, M.S. Cytokine networks and T-cell subsets in inflammatory bowel diseases. Inflamm. Bowel Dis. 22, 1157–1167 (2016).
Ben-Horin, S. & Chowers, Y. Tailoring anti-TNF therapy in IBD: drug levels and disease activity. Nat. Rev. Gastroenterol. Hepatol. 11, 243–255 (2014).
Guerra, I. & Bermejo, F. Management of inflammatory bowel disease in poor responders to infliximab. Clin. Exp. Gastroenterol. 7, 359–367 (2014).
Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).
Garbers, C. et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 23, 85–97 (2012).
Richards, C.D. The enigmatic cytokine oncostatin m and roles in disease. ISRN Inflamm. 2013, 512103 (2013).
Hermanns, H.M. Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology. Cytokine Growth Factor Rev. 26, 545–558 (2015).
Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
Beigel, F. et al. Oncostatin M mediates STAT3-dependent intestinal epithelial restitution via increased cell proliferation, decreased apoptosis and upregulation of SERPIN family members. PLoS One 9, e93498 (2014).
Sanchez, A.L. et al. Adenoviral transfer of the murine oncostatin M gene suppresses dextran-sodium sulfate-induced colitis. J. Interferon Cytokine Res. 23, 193–201 (2003).
Haberman, Y. et al. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J. Clin. Invest. 124, 3617–3633 (2014).
Vanhove, W. et al. Strong upregulation of AIM2 and IFI16 inflammasomes in the mucosa of patients with active inflammatory bowel disease. Inflamm. Bowel Dis. 21, 2673–2682 (2015).
Arijs, I. et al. Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment. PLoS One 4, e7984 (2009).
Galamb, O. et al. Reversal of gene expression changes in the colorectal normal-adenoma pathway by NS398 selective COX2 inhibitor. Br. J. Cancer 102, 765–773 (2010).
Planell, N. et al. Transcriptional analysis of the intestinal mucosa of patients with ulcerative colitis in remission reveals lasting epithelial cell alterations. Gut 62, 967–976 (2013).
D'Haens, G.R. et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn′s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am. J. Gastroenterol. 106, 199–212 (2011).
Arijs, I. et al. Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis. Gut 58, 1612–1619 (2009).
Toedter, G. et al. Gene expression profiling and response signatures associated with differential responses to infliximab treatment in ulcerative colitis. Am. J. Gastroenterol. 106, 1272–1280 (2011).
Sandborn, W.J. et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 137, 1250–1260 (2009).
Sandborn, W.J. et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 146, 85–95 (2014).
Bindea, G. et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25, 1091–1093 (2009).
Owens, B.M.J. et al. CD90+ Stromal cells are non-professional innate immune effectors of the human colonic mucosa. Front. Immunol. 4, 307 (2013).
Owens, B.M.J. Inflammation, innate immunity, and the intestinal stromal cell niche: opportunities and challenges. Front. Immunol. 6, 319 (2015).
Vicente-Suarez, I. et al. Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells. Mucosal Immunol. 8, 141–151 (2015).
Peduto, L. et al. Inflammation recapitulates the ontogeny of lymphoid stromal cells. J. Immunol. 182, 5789–5799 (2009).
Baptista, A.P. et al. Colonic patch and colonic SILT development are independent and differentially regulated events. Mucosal Immunol. 6, 511–521 (2013).
Astarita, J.L., Acton, S.E. & Turley, S.J. Podoplanin: emerging functions in development, the immune system, and cancer. Front. Immunol. 3, 283 (2012).
Fletcher, A.L., Acton, S.E. & Knoblich, K. Lymph node fibroblastic reticular cells in health and disease. Nat. Rev. Immunol. 15, 350–361 (2015).
Kullberg, M.C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).
Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568 (2014).
Kullberg, M.C. et al. Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect. Immun. 69, 4232–4241 (2001).
Arnold, I.C. et al. CD11c+ monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23. Mucosal Immunol. 9, 352–363 (2016).
Brolund, L., Küster, A., Korr, S., Vogt, M. & Müller-Newen, G. A receptor fusion protein for the inhibition of murine oncostatin M. BMC Biotechnol. 11, 3 (2011).
Feagan, B.G. et al. Ustekinumab as induction and maintenance therapy for Crohn's Disease. N. Engl. J. Med. 375, 1946–1960 (2016).
Ryan, R.E. et al. Oncostatin M binds to extracellular matrix in a bioactive conformation: implications for inflammation and metastasis. Cytokine 72, 71–85 (2015).
Bottini, N. & Firestein, G.S. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. 9, 24–33 (2013).
McLean, L.P. & Cross, R.K. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment. Expert Rev. Gastroenterol. Hepatol. 8, 223–240 (2014).
Murdaca, G. et al. Infection risk associated with anti-TNF-α agents: a review. Expert Opin. Drug Saf. 14, 571–582 (2015).
Komori, T., Tanaka, M., Senba, E., Miyajima, A. & Morikawa, Y. Deficiency of oncostatin M receptor β (OSMRβ) exacerbates high-fat diet-induced obesity and related metabolic disorders in mice. J. Biol. Chem. 289, 13821–13837 (2014).
Hamada, T. et al. Oncostatin M gene therapy attenuates liver damage induced by dimethylnitrosamine in rats. Am. J. Pathol. 171, 872–881 (2007).
Nakamura, K., Nonaka, H., Saito, H., Tanaka, M. & Miyajima, A. Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice. Hepatology 39, 635–644 (2004).
Kubin, T. et al. Oncostatin M is a major mediator of cardiomyocyte dedifferentiation and remodeling. Cell Stem Cell 9, 420–432 (2011).
Pöling, J. et al. Therapeutic targeting of the oncostatin M receptor-β prevents inflammatory heart failure. Basic Res. Cardiol. 109, 396 (2014).
Choy, E.H. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials. Arthritis Res. Ther. 15, R132 (2013).
Tanaka, M. & Hirabayashi, Y. Targeted disruption of oncostatin M receptor results in altered hematopoiesis. Blood 102, 3154–3162 (2003).
Morikawa, Y. et al. Essential function of oncostatin m in nociceptive neurons of dorsal root ganglia. J. Neurosci. 24, 1941–1947 (2004).
Pohin, M. et al. Oncostatin M overexpression induces skin inflammation but is not required in the mouse model of imiquimod-induced psoriasis-like inflammation. Eur. J. Immunol. 46, 1737–1751 (2016).
Guilloteau, K. et al. Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α recapitulates some features of psoriasis. J. Immunol. 184, 5263–5270 (2010).
Gazel, A. et al. A characteristic subset of psoriasis-associated genes is induced by oncostatin-M in reconstituted epidermis. J. Invest. Dermatol. 126, 2647–2657 (2006).
Boniface, K. et al. Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation. J. Immunol. 178, 4615–4622 (2007).
Langdon, C. et al. Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo. Am. J. Pathol. 157, 1187–1196 (2000).
Hui, W., Cawston, T.E., Richards, C.D. & Rowan, A.D. A model of inflammatory arthritis highlights a role for oncostatin M in pro-inflammatory cytokine-induced bone destruction via RANK/RANKL. Arthritis Res. Ther. 7, R57–R64 (2005).
Hui, W., Rowan, A.D., Richards, C.D. & Cawston, T.E. Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo. Arthritis Rheum. 48, 3404–3418 (2003).
Hintzen, C., Quaiser, S., Pap, T., Heinrich, P.C. & Hermanns, H.M. Induction of CCL13 expression in synovial fibroblasts highlights a significant role of oncostatin M in rheumatoid arthritis. Arthritis Rheum. 60, 1932–1943 (2009).
Ott, C. & Schölmerich, J. Extraintestinal manifestations and complications in IBD. Nat. Rev. Gastroenterol. Hepatol. 10, 585–595 (2013).
Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).
Becker, C., Fantini, M.C. & Neurath, M.F. High resolution colonoscopy in live mice. Nat. Protoc. 1, 2900–2904 (2007).
Izcue, A. et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008).
Uhlig, H.H. et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J. Immunol. 177, 5852–5860 (2006).
West, N.R., Murray, J.I. & Watson, P.H. Oncostatin-M promotes phenotypic changes associated with mesenchymal and stem cell-like differentiation in breast cancer. Oncogene 33, 1485–1494 (2014).
West, N.R., Murphy, L.C. & Watson, P.H. Oncostatin M suppresses oestrogen receptor-α expression and is associated with poor outcome in human breast cancer. Endocr. Relat. Cancer 19, 181–195 (2012).
Acknowledgements
We thank J. Middleton, S. Rogatti Granados, C. Arancibia, P. Siddhanathi, J. Chivenga, N. Charumbira, J. Schulthess, C. Pearson, and S. Spieckermann for excellent technical support, patient-sample collection, and lab management. We thank H. Uhlig and all members of the laboratory for valuable discussions and support. We also thank V. Malmstrom and E. Thompson for critical review of this manuscript. We thank V. Cerundolo for providing IL-1R1 knockout mice. We gratefully acknowledge the contributions of the Oxford Radcliffe and GI Biobanks and the Oxford IBD cohort study, which are supported by the NIHR Oxford Biomedical Research Centre (grant no. HBRWAE04 Task HB81.G). We thank the flow cytometry core-facility staff at the University of Oxford Translational Gastroenterology Unit and Kennedy Institute of Rheumatology, as well as the staff of the Kennedy Institute histology core facility for excellent tissue preparation. We thank all volunteers, patients, and their families for agreeing to contribute to this study. N.R.W. was supported by an Irvington Institute Postdoctoral Fellowship (Cancer Research Institute). A.N.H. was supported by a European Molecular Biology Organization (EMBO) long-term fellowship (ALTF 116-2012) and a Marie Curie fellowship (FP7-PEOPLE-2012-IEF, proposal 330621). B.M.J.O. is a lecturer at Somerville College, University of Oxford. S.T. was supported by the Ecole Normale Supérieure of Lyon and the French Ministry of Education. R.J.O. and N.R. are supported by Medical Research Council grant no. MR/K018779/1. M.C. and K.J.M. were supported by the Edward Penley Abraham Trust. K.J.M. is supported by the Wellcome Trust (Investigator Award 102972). F.P. is supported by the Wellcome Trust and Foundation Louis Jeantet.
Author information
Authors and Affiliations
Consortia
Contributions
N.R.W., A.N.H., B.M.J.O., and F.P. contributed to study conception and design, data analysis, and manuscript production. N.R.W. and A.N.H. designed, executed, and analyzed experiments. S.J.B., C.C., and A.A.K. performed histological assays. B.L., F.B., C.B., and S.E.P. contributed clinical trial data and analysis. S.B., M.C., and K.J.M. provided data on the cytokine requirements of the Hh + α-IL-10R model of IBD. D.G. and G.M.-N. designed the OR-Fc protein construct. N.R. and R.J.O. designed the strategy for OR-Fc production and generated the final protein. S.T. contributed to intestinal stromal cell experiments. K.S. and G.R. contributed to preclinical mouse experiments. J.P. conducted mouse intestinal organoid experiments. M.F. contributed to the establishment of human intestinal stromal cell cultures. S.K. and S.P.L.T. provided clinical guidance and contributed to patient-sample collection. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
N.R.W., A.N.H., B.M.J.O., and F.P. are inventors of patents relating to OSM as a therapeutic target for IBD. S.K. has received honoraria and/or research support from Allergan, Abbvie, Astra-Zeneca, ChemoCentryx Inc., Dr Falk Pharma, Ferring, Gilead, GSK, Merck, Mitsubishi-Tanabe Pharma, Pfizer, and Vifor Pharma. S.P.L.T. has received research support from Abbvie, IOIBD, Lilly, UCB, Vifor, and the Norman Collison Foundation. S.P.L.T. receives consulting fees from Abbvie, Amgen, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chemocentryx, Cosmo, Ferring, Giuliani SpA, GSK, Lilly, MSD, Neovacs, NovoNordisk, Norman Collison Foundation, Novartis, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Shire, Sigmoid Pharma, Takeda, Topivert, UCB, VHsquared, and Vifor Pharma. S.P.L.T. has received speaker fees from Abbvie, Biogen, Ferring, and Takeda. B.L., F.B., C.B., and S.E.P. are employees of Janssen Research and Development LLC. S.B. and M.C. are currently employees of GSK. F.P. has received research support or consultancy fees (unrelated to this work) from Eli Lilly, Janssen, GSK, Medimmune, Compugen and UCB.
Supplementary information
Supplementary Text and Figures
Supplementary Methods, Supplementary Figures 1–11 and Supplementary Tables 1–4 (PDF 7536 kb)
Rights and permissions
About this article
Cite this article
West, N., Hegazy, A., Owens, B. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease. Nat Med 23, 579–589 (2017). https://doi.org/10.1038/nm.4307
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.4307
This article is cited by
-
Linking gene expression to clinical outcomes in pediatric Crohn’s disease using machine learning
Scientific Reports (2024)
-
The neutrophil–osteogenic cell axis promotes bone destruction in periodontitis
International Journal of Oral Science (2024)
-
Extramedullary hematopoiesis in cancer
Experimental & Molecular Medicine (2024)
-
Strategies for targeting cytokines in inflammatory bowel disease
Nature Reviews Immunology (2024)
-
Interleukins in Epilepsy: Friend or Foe
Neuroscience Bulletin (2024)