2nd Annual BMRP Investigator Meeting - Abstract

The Role of Tumor Necrosis Factor Receptors (TNFRs) of Non-Lymphoid Cells Under Inflammatory Condition

Emiko Mizoguchia, Ken Sugimoto, Atsushi Mizoguchi and Daniel K. Podolsky

Department of Pathology, Massachusetts General Hospital (Boston, U.S.A.)

Ligation of TNFR1 and/or TNFR2 with TNFa plays a critical role in the pathogenesis of human inflammatory bowel disease (IBD).  Although it is clear that TNFa/TNFRs interactions are required for the major pathogenic effects, it remains unclear whether all cell types activated through TNFR-associated signaling cascades are involved in the pathogenesis of IBD.  Utilizing a dextran sulfate sodium (DSS)-induced acute colitis model in B6, TNFR1 knockout (KO), TNFR2 KO and TNFR1 and TNFR2 double KO (DKO) mice, we found that both TNFR1 and TNFR2 contribute to the prevention of lethal intestinal damage.  To further examine the functional importance of TNFRs on non-lymphoid cells, DSS colitis was induced in TNFR1- or/and TNFR2-deficient RAG-1 double (or triple knockout) mice and bone marrow (BM) chimera mice in which RAG x TNFR1 DKO and RAG x TNFR2 DKO mice received BM transplant from RAG KO mice.

The results of these studies suggest that TNFR1 expressed on non-lymphoid, myeloid lineage cells present in colonic lamina propria (LP) is a critical regulator for recovering from DSS induced acute colitis.  Interestingly, the BM cell transplantation from RAG KO mice led to significant upregulation of MAPKp42/p44 phosphorylation in the colonic epithelial cells (CEC), but not LP cells of the recipient TNFR1 x RAG DKO mice on day 6 of DSS treatment.  These observations suggest that factors produced by LP cells might contribute to the activation of MAP-kinase cascades in CEC.

In summary, these studies indicate that TNFR1-mediated signaling cascade in colonic LP myeloid lineage cells might act as beneficial factors in the development of colitis by enhancing innate immune responses with the activation of MAPK signaling pathway in CEC.

aPrincipal Investigator