Abstract Background Alpha-defensin 1 (DEFA1), stored in neutrophils, is implicated in the pathogenesis of ulcerative colitis (UC). The copy number of DEFA1 has been associated with the clinical severity of UC; however, the mechanisms by which DEFA1 contributes to colonic inflammation remain unclear. In this study, we investigated the role and mechanism of DEFA1 in an experimental mouse model of colitis. Methods Transgenic (Tg) mice expressing human DEFA1 under the control of the CD11b promoter were generated. Colitis was induced using a dextran sodium sulfate (DSS) model. A comprehensive analysis was conducted, including survival rate, body weight, intestinal length, clinical disease activity index, histological colitis scores, and gene expression profiling of intestinal tissues via RNA sequencing and real-time polymerase chain reaction (PCR). Protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results Mice were divided into two groups: a Tg group with high DEFA1 copy number and expression, and control littermates lacking DEFA1 expression. In the DSS-induced colitis model, Tg mice exhibited significantly higher mortality, greater clinical disease activity, and worse histological scores compared to controls. RNA sequencing of intestinal tissues revealed increased expression of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the Tg group. However, validation by real-time PCR and ELISA showed that only IL-1β was significantly elevated, with no significant difference in TNF-α levels between groups. Conclusion A high copy number of DEFA1 may promote the expression of inflammatory cytokines such as IL-1β and play a key role in the exacerbation of intestinal inflammation. Conflict of interest: Dr. Kanmura, Shuji: No conflict of interest Morinaga, Yuko: No conflict of interest Mori, Satoshi: No conflict of interest Maeda, Nobuhisa: No conflict of interest Kojima, Issei: No conflict of interest Tanaka, Akihito: No conflict of interest Maeda, Hidehito: No conflict of interest Sasaki, Fumisato: No conflict of interest
Kanmura et al. (2026) studied this question.