Distinct effects of p38alpha deletion in myeloid lineage and gut epithelia in mouse models of inflammatory bowel disease

Abstract

Background & aims: p38Alpha is a mitogen-activated protein kinase that mediates inflammatory responses, but its role in inflammatory bowel disease is unclear. The effects of p38alpha inhibitors have been inconsistent in animal models and clinical studies of inflammatory bowel disease, possibly arising from the different functions of p38alpha in different tissues or cell types. We investigated the effects of p38alpha inhibition in myeloid versus colonic epithelium.

Methods: We studied mice with myeloid cell-specific and intestinal epithelial cell-specific disruption of p38alpha (LtrLys(Cre)-p38alpha(Delta/Delta) mice and Villin(Cre)-p38alpha(Delta/Delta) mice), as well as p38beta, gamma, and delta knockout. Colitis was induced using dextran sodium sulfate or trinitrobenzene sulfonic acid (TNBS).

Results: Mice with myeloid cell-specific deletion of p38alpha had less inflammation and an improved disease condition compared with wild-type mice, whereas mice with intestinal epithelial cell-specific deletion of p38alpha had increased progression of colitis that resulted from disrupted intestinal epithelial homeostasis. The distinct effects of p38alpha disruption in different tissue types might underlie the unsuccessful therapeutic application of p38 inhibitors to colitis. We found that a gamma-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: p38Alpha has distinct functions in mouse myeloid cells versus colonic epithelium; these differences should be taken into consideration in defining the role of p38alpha in inflammation and developing p38 inhibitors as therapeutics.