We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild-type (WT) mice. MyD88-/- mice administered cerulein developed severe pancreatitis as compared with MyD88+/+ WT mice. The number of IL-10-expressing CD11b+Gr-1high cells in cerulein-administered MyD88-/- mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4+ T cells as compared with that in control MyD88+/+ mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non-bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis.
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