Carbon monoxide (CO) can provide beneficial anti-inflammatory effects during organ transplantation. In a murine renal allograft model, treatment with Carbon monoxide-releasing molecule-3 (CORM-3) reduces cellular infiltrates while improving long-term renal function and survival. However, the mechanisms governing CORM-3's immunological regulation is unknown. In this study we demonstrate that CORM-3 can decrease dendritic cell (DC) maturity and infiltration. According to flow cytometry results, murine bone marrow-derived DCs demonstrated low expression levels of CD40, CD80, CD83, MHC-II and high levels of CD205 upon treatment with CORM-3 in comparison with inactivated CORM-3 and untreated controls in vitro (P<0.05). Following in vivo induction of ischemia and reperfusion injury (IRI) using a one-hour renal hilar-clamp model, DC infiltration was also significantly decreased under CORM-3 treatment vs. controls (P<0.05) as determined by immunohistochemistry with CD11c and CD40. In addition, preliminary RT-PCR results suggest that CORM-3 downmodulates expression levels of TLR4. Recognizing that TLR4 is an important surface molecule involved in DC signaling and activation, our ongoing studies aim to determine the direct and/or indirect link between CORM-3 and TLR4 surface expression on DCs, to verify the relationship with CORM-3 therapy and DC immaturity with regards to transplant-related stress.

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