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pubmed:abstractText |
Opioid receptor agonists induce broad immunomodulatory activity, which substantially alters host defense and the inflammatory response. Previous studies have shown that the MOR selective agonist DAMGO has the capacity to increase the expression of the proinflammatory chemokines CCL2, CCL5, and CXCL10 in human PBMCs. NF-?B is a transcription factor that plays a pivotal role in innate and adaptive immune responses. We report that NF-?B is a vital player in the DAMGO-induced, MOR-mediated regulation of chemokine expression. Results show that NF-?B inhibitors prevent the induction of CCL2 expression in response to DAMGO administration and that the NF-?B subunit, p65, is phosphorylated at serine residues 311 and 536 in response to MOR activation. Furthermore, we demonstrate that PKC? is phosphorylated following DAMGO-induced MOR activation, and this kinase is essential for NF-?B activation as well as CCL2 expression and transcriptional activity. Finally, ChIP analysis shows that DAMGO administration induces binding of p65 to the enhancer region of the CCL2 promoter. These data are consistent with the notion that MOR activation promotes a proinflammatory response, which involves NF-?B activation. Our results also suggest a significant and novel role for PKC? as an essential participant in the MOR-mediated regulation of proinflammatory chemokine expression.
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