Anti-TNF Therapy Induces CD4 ⁺ T-Cell Production of IL-22 and Promotes Epithelial Repairs in Patients with Crohn's Disease

Background Anti-tumor necrosis factor (TNF) therapy appears to be effective in the treatment of Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract. However, the mechanisms involved are not completely understood. Methods Fifty-seven active CD patients were enrolled, and cytokine profiles in colonic biopsies of patients with active CD receiving anti-TNF monoclonal antibody (mAb) (infliximab [IFX]) treatment were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Colonic biopsies of active CD patients and healthy donors were cultured with IFX in vitro, and cytokine profiles were measured by qRT-PCR. Peripheral blood (PB)-CD4 ⁺ T cells were stimulated with anti-CD3 and anti-CD28 mAbs in the presence of human immunoglobin (HIg), IFX, recombinant human TNF-α converting enzyme (rhTACE), and aryl hydrocarbon receptor (AhR) inhibitor (CH-223191), respectively, to determine interleukin (IL)-22 expression by CD4 ⁺ T cells. Caco2 cells were also utilized to study their potential role in modulating epithelial cell barrier repairs in vitro. Results IFX therapy markedly upregulated IL-22 mRNA expression in the gut mucosa of CD patients. In vitro treatment with IFX greatly promoted CD CD4 ⁺ T cells to express IL-22, which was inhibited by rhTACE, indicating that reverse signaling through binding to membrane-bound TNF mediates anti-TNF-induced IL-22 expression of CD CD4 ⁺ T cells. However, blockade of AhR markedly inhibited anti-TNF-induced IL-22 ⁺ CD4 ⁺ T (Th22) cell differentiation in CD patients. Moreover, treatment with IL-22 induced intestinal epithelial cell expression of tight junction proteins (eg, claudin1 and ZO-1) and facilitated transepithelial resistance, indicating that IL-22 protects intestinal mucosa from inflammation via maintenance of epithelial barrier integrity. Conclusions Our results uncover a novel mechanism whereby anti-TNF therapy upregulates IL-22 production in CD patients through promoting Th22 cell differentiation and contributes to intestinal epithelial barrier repairs.