WIN55,212-2 inhibits production of CX3CL1 by human astrocytes: involvement of p38 MAP kinase.
CX3CL1 (fractalkine) has been shown not only to be neuroprotective but also may play a role in HIV-1-associated neuropathogenesis. In this study, we found that production of CX3CL1 by human astrocytes stimulated with interleukin (IL)-1beta was inhibited in a concentration-dependent manner following pretreatment with the synthetic cannabinoid WIN55,212-2. The CB(2) receptor selective antagonist SR144528 significantly inhibited WIN55,212-2-mediated suppression of CX3CL1, suggesting a CB(2)-receptor-related mechanism. IL-1beta triggered the activation of p38 and ERK1/2 (p44/42) MAP kinase (MAPK) signaling pathways, but WIN55,212-2 mainly inhibited p38 MAPK phosphorylation. This finding was mirrored in experiments using known inhibitors of these MAPKs, suggesting that the suppression of CX3CL1 production by WIN55,212-2 involves inhibition of signaling via p38 MAPK. Our results support the concept that synthetic cannabinoids have anti-inflammatory properties and that these agents may have therapeutic potential for certain neuroinflammatory disorders.
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Department of Medicine, The Center for Infectious Diseases & Microbiology Translational Research, University of Minnesota Medical School, Minneapolis, MN 55455, USA. sheng008@umn.edu
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D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D048588:Benzoxazines / Q000494:pharmacology*; D015153:Blotting, Western; D001892:Camphanes / Q000494:pharmacology; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000096:biosynthesis / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D048588:Benzoxazines; C515538:CX3CL1 protein, human; D001892:Camphanes; D054428:Chemokine CX3CL1; D009025:Morpholines; D009281:Naphthalenes; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D048051:p38 Mitogen-Activated Protein Kinases