Extra-Adrenal Glucocorticoid Synthesis in Mucosal Tissues and Its Implication in Mucosal Immune Homeostasis and Tumor Development

While glucocorticoids (GC) exert broad effects on metabolism, behavior and immunity, local production of even small amounts of GC, which may act in a paracrine or even autocrine manner, enable a specific site of the body to regulate their exposure to GC according to their specific needs. Mucosal tissues, for example, are at the borderline to the outside world, and are therefore in constant contact with either harmless foreign particles or potentially pathogenic microorganisms, which might provoke devastating inflammatory disorders due to chronic stimulation of the mucosal immune system. Increasing the local concentration of immunoregulatory GC by extra-adrenal de novo GC synthesis or local reactivation of inactive serum metabolites provides a protective mechanism to either restore homeostasis after clearance of infection or to regulate the critical balance between immunity and tolerance

Crucial Involvement of the CCR2/CCL2 Interactions in Azoxymethane/Dextran Sodium Sulfate-induced Colon Carcinogenesis in Mice

Azoxymethane (AOM) administration followed by repetitive dextran sulfate sodium (DSS) ingestion causes chronic colonic inflammation with macrophage infiltration and enhanced expression of a macrophage-tropic chemokine, CCL2, in wild-type (WT) mice. These mice eventually develop multiple colon tumors. In contrast, mice deficient in CCR2, a specific receptor for CCL2, exhibited less macrophage infiltration and attenuated tumor formation. WT mice transplanted with CCR2-deficient bone marrow developed fewer tumors after AOM and DSS treatment than either WT or CCR2-deficient mice transplanted with WT bone marrow. Furthermore, when injected to WT mice with multiple colon tumors, a CCL2 antagonist expression vector attenuated macrophage and granulocyte infiltration, and eventually reduced the numbers and sizes of tumors. These results implied the crucial involvement of the CCL2-CCR2 interactions in the development and progression of colon carcinoma associated with chronic inflammation