Distinct Effects of p38α Deletion in Myeloid Lineage and Gut Epithelia in Mouse Models of Inflammatory Bowel Disease

Abstract

Background & Aims: p38α is a mitogen-activated protein kinase that mediates inflammatory responses, but its role in inflammatory bowel disease is unclear. The effects of p38α inhibitors have been inconsistent in animal models and clinical studies of inflammatory bowel disease, possibly arising from the different functions of p38α in different tissues or cell types. We investigated the effects of p38α inhibition in myeloid versus colonic epithelium. Methods: We studied mice with myeloid cell-specific and intestinal epithelial cell-specific disruption of p38α (LtrLysCre-p38αΔ/Δ mice and VillinCre-p38αΔ/Δ mice), as well as p38β, γ, and δ knockout. Colitis was induced using dextran sodium sulfate or trinitrobenzene sulfonic acid (TNBS). Results: Mice with myeloid cell-specific deletion of p38α had less inflammation and an improved disease condition compared with wild-type mice, whereas mice with intestinal epithelial cell-specific deletion of p38α had increased progression of colitis that resulted from disrupted intestinal epithelial homeostasis. The distinct effects of p38α disruption in different tissue types might underlie the unsuccessful therapeutic application of p38 inhibitors to colitis. We found that a γ-secretase inhibitor, which functions opposite that of a p38 inhibitor in the regulation of intestinal epithelial homeostasis, can significantly improve the effects of a p38 inhibitor in reducing colitis. Conclusions: p38α has distinct functions in mouse myeloid cells versus colonic epithelium; these differences should be taken into consideration in defining the role of p38α in inflammation and developing p38 inhibitors as therapeutics. © 2010 AGA Institute.