Date of Award
Doctor of Philosophy (PhD)
Timothy L Denning
Inflammatory bowel disease (IBD) is a multifactorial, chronic disease that affects approximately 1.5 million people in the United States . It presents with inflammation of the intestine with unknown etiology. Its two main forms are Crohn’s disease (CD), which can affect any part of the GI tract, and ulcerative colitis (UC), which impacts primarily the colon. Several important factors are implicated in the pathogenesis of IBD, one factor being dysregulation of the immune system. This dysregulation results in the accumulation and stimulation of innate and adaptive immune cells and subsequent release of soluble factors, including pro-inflammatory cytokines. One of these cytokines is a member of the IL-36 cytokine family, IL-36γ, which is overexpressed in human IBD and experimental models of colitis. In this study, we explored the role of IL-36γ in promoting CD4+ T cell activation and cytokine secretion. We found that IL-36γ stimulation of naïve CD4+ T cells significantly induced IFNγ expression in vitro and was associated with augmented intestinal inflammation in vivo using the T cell transfer model of colitis. Using IFNγ-/- naive T cells, we observed a dramatic decrease in the ability of these cells to produce TNFα and IL-12. Moreover, the transfer of these cell did not cause robust colitis. These data not only suggest that IL-36γ is a master regulator of a pro-inflammatory cytokine network involving IFNγ, TNFα and IL-12, but also highlight the importance of targeting IL-36y and IFNy as therapeutic approaches. Our studies have broad implications in relation to targeting of specific cytokines in human IBD.
Maarouf, Maya, "IL-36/IL-36R Signaling Promotes CD4+ T Cell-Dependent Colitis via Pro-Inflammatory Cytokine Production." Dissertation, Georgia State University, 2023.