IL37 is a newly described member of the IL-1 family,which is anti-inflammatory by its inhibition of pro-inflammatory cytokine production. While human IL37 has no murine homologue, shared amino acid sequences with IL-18 allows binding to both human and mouse IL-18 receptors as well as IL-18 binding protein (IL-18BP).IL37 binds to IL-18RΑ with low affinity and also can form a trimeric complex with IL-18BP and IL-18RΒ to block IL-18 activity. IL37 is expressed by mononuclear cells, dendritic cells, but to date no report has described IL37 expression in renal tubular epithelial cells (TEC) nor any capacity to attenuate kidney ischemia reperfusion injury (IRI). We have found that human and mouse TEC have basal expression of IL-18Ra, IL-18RΒ and IL-18BP, and TNFa and hypoxia inducible expression of IL-18. Exogenous IL37 (300ng/mL) down-regulated the IL-18 induced expression of TNFa, IL-6 and IL-1Β in murine NG TEC (p <0.05) and human PT2 TEC (p <0.01). Importantly, for the first time, we found that LPS, IFN-r and IL-18 induced the expression of IL37 in human PT2 TEC. Consistent with an inhibitory role, mRNA silencing of IL-37 in TEC resulted in augmented mRNA expression of TNFa, IL-6 and IL-1Β induced by IL-18. In contrast, enhanced expression of IL37 by human PT2 TEC transfected with pCMV6-XL5-IL37 plasmid decreased mRNA expression of pro-inflammatory cytokines (TNFa, IL-6 and IL-1Β) induced by IL-18 (p<0.05). We then tested whether IL37 could reduce renal IRI in vivo using a uni-nephrectomy mouse model and renal artery clamping (45 min, 33°C). Mice transfected with pCMV6-XL5-IL37(tail vein, 24 hours prior). Augmented kidney expression of IL37 in these mice resulted in lower serum creatinine levels at 48 hours compared to vector controls (76±60umol/l vs 166±57umol/l, n=4-5/grp, p=0.05). Our results confirm that TEC express IL-18 and IL-18R, and for the first time report that TEC express the IL-18 contra-regulatory proteins IL37 and IL-18BP. Collectively these data suggest IL37 production by TEC may be a previously unrecognized intra-renal control mechanism to attenuate inflammation. Augmenting kidney IL37 levels may represent a novel strategy that exploits an endogenous pathway to prevent renal inflammatory injury and IRI during transplantation.

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