Role of intraperitoneal cell-traffic and TGF superfamily members in inflammatory bowel diseases

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The aim of this study was to clarify the mechanism of inflammatory cell infiltration in mouse model of inflammatory bowel disease by focusing the cell trafficking and immune system in the peritoneal cavity. Initially we found great loss of peritoneal macrophages in peritoneal exudate after induction of colitis and increased number of immature granulocyte-type cells. We investigated the specific recruitment of peritoneal macrophages (PMФs) by adoptive transfer of fluorescence-labeled peritoneal macrophages, and their expression of chemokine receptors. PMФs aggregated at the site of injured serosal side of the colon. The chemokine receptor CCR8 was upregulated in the aggregating PMФs when compared with naive PMФs. The upregulation of CCR8 was also observed in PMФs, but not in bone marrow-derived macrophages, treated with inflammatory stimulants including bacterial components and cytokines. Importantly, CCL1, the ligand for CCR8, a product of both PMФs and peritoneal mesothelial cells (PMCs) following inflammatory stimulation, was a potent enhancer of CCR8 expression. LPS-challenged PMФs also produced a TGF-superfamily member activin. Cell aggregation involving PMФand PMCs was induced in vitro in the presence of CCL1. CCR8 gene deficient mice or mice treated with anti-CCL1 neutralizing antibody exhibited significantly reduced serosal macrophage accumulation. Our study now establishes a unique autocrine activation system in PMФ and the mechanism for recruitment of PMФs together with PMCs via CCL1/CCR8, as immune responses of peritoneal cavity. Here we found an efficient defense mechanism as a specific function of peritoneal macrophages when inflammatory or surgical stress reaches to the deep inside of the body.