Pancreatic beta cells undergoing metabolic and inflammatory stress express islet-derived cytokines or “isletokines” which can induce immune cell infiltration and cellular damage leading to loss of islet cell function. We and others have shown that toll-like receptor (TLR) 4 in islets can mediate metabolic and inflammatory response to DAMPs under diabetic conditions and in islet cell transplantation. Here we show that metabolic and inflammatory conditions result in induction and suppression of expression of multiple members of the TLR family in both MIN6 beta-cell line and mouse islets. Among upregulated TLRs, the endosomal nucleic acid-sensing TLR3 was most highly induced (up to 5 fold) in response to cytokine cocktail IL-1beta, TNF-alpha, and IFN-gamma in the presence of high glucose. Induction of TLR3 expression was blocked by PI3 kinase inhibitor wortmannin and unaffected by mTOR inhibitor rampamycin, calcineurin inhibitor FK506, and NF-κB inhibitor BMS345541. Immunoblot analyses confirmed that TLR3 but not TLR4 protein expression was wortmannin sensitive. These data indicate that TLR3 is upregulated by PI3 kinase signaling in islet beta cells in response to inflammatory conditions. As the endosomal TLR3 signaling is known to sense nucleic acids as well as influence glucose homeostasis, we propose that beta cells may sense DNA damage to induce isletokines to mediate local inflammatory responses during metabolic and inflammatory stress. Further investigations are warranted to decipher signaling pathways and molecular targets of TLR3 signaling to alleviate islet inflammation and improve beta-cell function.


J.D.Mattke: None. B.Naziruddin: None. M.C.Lawrence: None.

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