Author(s): Husted TL, Govindaswami M, Oeltgen PR, Rudich SM, Lentsch AB
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Abstract BACKGROUND: delta-Opioid agonists have been shown to attenuate ischemic organ injury in multiple models. The purpose of the present study was to determine if delta-opioid agonists could inhibit proinflammatory cytokine production by macrophages. MATERIAL AND METHODS: Murine macrophages (RAW 264.7) were pretreated for 4 h with media, a dose range (10(-4) to 10(-7) M) of DADLE ([D-Ala2], D-Leu5]-enkephalin, a nonspecific delta-opioid receptor agonist), a dose range (10(-4) to 10(-7) M) of DPDPE ([D2,5Pen]-enkephalin, a specific delta1-opioid receptor agonist), or a dose range (10(-4) to 10(-7) M) of Deltorphin-Dvariant (a specific delta2 opioid receptor agonist) and then incubated with 0.1 microg/ml lipopolysaccharide (LPS) for 1 or 4 h. Cytokine levels were measured by enzyme-linked immunosorbent assay. Activation of NF-kappaB, AP-1, and p38 MAPK were determined by mobility shift assays and Western blot. RESULTS: LPS induced significant increases in TNFalpha and MIP-2 production. Deltorphin-Dvariant, but not DADLE or DPDPE, dose-dependently reduced both TNFalpha and MIP-2 production. Deltorphin-Dvariant did not alter activation of the transcription factors NF-kappaB or AP-1, but greatly reduced activation of p38 MAPK. CONCLUSIONS: The data show that delta2- but not delta1-opioid agonists suppress LPS-induced p38 MAPK activation and expression of TNFalpha and MIP-2.
This article was published in J Surg Res
and referenced in Virology & Mycology