The cytokine interleukin-22 (IL-22) is a critical regulator of epithelial homeostasis. It has been implicated in multiple aspects of epithelial barrier function, including regulation of epithelial cell growth and permeability, production of mucus and antimicrobial proteins (AMPs), and complement production. In this review, we focus specifically on the role of IL-22 in the intestinal epithelium. We summarize recent advances in our understanding of how IL-22 regulates homeostasis and host defense, and we discuss the IL-22 pathway as a therapeutic target in diseases of the intestine, including inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), and cancer.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Current therapies, such as corticosteroids, immunosuppressants, and anti–tumor necrosis factor (TNF) antibodies, are not universally effective at induction and maintenance of remission,¹ x 1 Ordas, I., Eckmann, L., Talamini, M. et al. Ulcerative colitis. Lancet. 2012; 380: 1606–1619 Abstract | Full Text | Full Text PDF | PubMed | Scopus (466) | Google Scholar See all References with ≈25% of patients requiring colectomy.² x 2 Bach, S.P. and Mortensen, N.J. Ileal pouch surgery for ulcerative colitis. World J Gastroenterol. 2007; 13: 3288–3300 Crossref | PubMed | Scopus (50) | Google Scholar See all References This variable response to treatment and disease progression may reflect significant heterogeneity in disease pathobiology.³ x 3 Ananthakrishnan, A.N. Personalizing therapy for inflammatory bowel diseases. Expert Rev Gastroenterol Hepatol. 2013; 7: 549–558 Crossref | PubMed | Scopus (5) | Google Scholar See all References ^{, 4} x 4 Loftus, E.V. Jr., Davis, K.L., Wang, C.C. et al. Treatment patterns, complications, and disease relapse in a real-world population of patients with moderate-to-severe ulcerative colitis initiating immunomodulator therapy. Inflamm Bowel Dis. 2014; 20: 1361–1367 Crossref | PubMed | Scopus (2) | Google Scholar See all References Improved stratification driven by patient heterogeneity may help guide choice of therapeutic intervention and enhance efficacy and safety.

Targeting interactions between α4β7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEβ7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. β1 and β7 integrin expression on circulating lymphocytes was similar across groups. TGF-β1 treatment induced expression of αE on both β7⁺ and β7⁻ T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4β7 can become αEβ7⁺. ITGAE gene polymorphisms did not alter protein induction following TGF-β1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-β, and increased TGF-β–responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline β7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE⁺ and αE⁻ T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4β7⁻, and α4β7⁺ T cells may upregulate αEβ7 in response to TGF-β once within the gut mucosa. Key Points Adhesion molecules are upregulated in inflamed intestinal mucosa in IBD patients. Baseline β7 expression does not impact αE induction or gene expression in T cells. Phospho-SMAD3 is increased in inflamed mucosa in IBD.

Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of α4β7 and αEβ7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of α4β7 and αEβ7 blockade using a combination of murine models of gut trafficking and longitudinal gene expression analysis in etrolizumab-treated patients with Crohn's disease (CD). Dual blockade of α4β7 and αEβ7 reduces CD8⁺ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-αEβ7 reduces epithelial:T cell interactions and promotes egress of activated T cells from the mucosa into lymphatics. Inflammatory gene expression is greater in human intestinal αEβ7⁺ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of α4β7 and αEβ7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention.

Multicellular cytokine networks drive intestinal inflammation and colitis-associated cancer (CAC). Interleukin-22 (IL-22) exerts both protective and pathogenic effects in the intestine, but the mechanisms that regulate this balance remain unclear. Here, we identify that IL-22 directly induces responsiveness to the IL-6 family cytokine oncostatin M (OSM) in intestinal epithelial cells (IECs) by activating STAT3 and upregulating the OSM receptor. In turn, OSM synergizes with IL-22 to sustain STAT3 activation in IECs and promote proinflammatory epithelial adaptation and immune cell chemotaxis to the inflamed intestine. Conditional deletion of the OSM receptor in IECs protects mice from both colitis and CAC, and pharmacological blockade of OSM attenuates established CAC. Thus, IL-22 and OSM form a pathogenic circuit that drives inflammation and tumorigenesis. Our findings reveal a previously unknown mechanism by which OSM supports intestinal pathology and highlight the IL-22–OSM axis as a promising therapeutic target for inflammatory bowel disease and CAC.