CD30 knockout attenuates experimental colitis by reducing inflammatory cytokine production.

Abstract

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by dysregulated T helper immune responses. Crohn’s disease is predominantly associated with excessive Th1 and Th17 responses, while ulcerative colitis displays a more heterogeneous immune profile. However, the molecular mechanisms underlying Th1 cell differentiation in intestinal inflammation remain incompletely understood. CD30, a member of the tumor necrosis factor receptor superfamily, has been implicated in various inflammatory conditions, yet its role in IBD pathogenesis has not been fully elucidated. OBJECTIVES: This study aimed to investigate the role of CD30 in experimental colitis and its regulation of Th1 cell differentiation through the NF-κB signaling pathway. METHODS: Acute colitis was induced in wild-type and CD30-deficient mice using 3% dextran sulfate sodium (DSS) for 7 days. CD30 expression in colonic tissues was assessed by immunohistochemistry, quantitative real-time PCR, and Western blot. Naive CD4 + T cells were isolated and stimulated under Th1-polarizing conditions with or without CD30 knockdown using small interfering RNA. Th1 differentiation was evaluated by flow cytometry with verification using T-bet and IL-17 A staining, and related transcription factors and cytokines were measured. The NF-κB signaling pathway was examined in lipopolysaccharide (LPS)-stimulated conditions. RESULTS: CD30 expression was significantly upregulated in DSS-induced colitis, correlating with increased Th1 markers including T-bet and IFN-γ. In vitro, CD30 knockdown markedly suppressed Th1 cell differentiation from naive CD4 + T cells, reducing IFN-γ + cell proportions among CD4 + T cells and downregulating T-bet, STAT4, and IL-12Rβ2 expression. Mechanistically, CD30 deficiency inhibited NF-κB pathway activation by reducing p65 phosphorylation and preventing IκBα degradation. In vivo, CD30-/- mice exhibited attenuated colitis severity with reduced disease activity index, improved colon length, decreased histological damage, and diminished Th1 cytokine production compared to wild-type littermates. CONCLUSIONS: CD30 promotes Th1 cell differentiation and exacerbates experimental colitis through NF-κB-dependent mechanisms. These findings identify CD30 as a potential therapeutic target for IBD treatment.