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The Journal of Immunology, 1998, 161: 2873-2880.
Copyright © 1998 by The American Association of Immunologists

{alpha}-Melanocyte-Stimulating Hormone Inhibits the Nuclear Transcription Factor NF-{kappa}B Activation Induced by Various Inflammatory Agents

Sunil K. Manna and Bharat B. Aggarwal1

Cytokine Research Laboratory, Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

{alpha}-Melanocyte-stimulating hormone ({alpha}-MSH) is a tridecapeptide found mainly in the brain, pituitary, and circulation. It inhibits most forms of inflammation by a mechanism that is not known. As most types of inflammation require activation of NF-{kappa}B, we investigated the effect of {alpha}-MSH on the activation of this transcription factor by a wide variety of inflammatory stimuli. Electrophoretic mobility shift assay showed that {alpha}-MSH completely abolished TNF-mediated NF-{kappa}B activation in a dose- and time-dependent manner. It also suppressed NF-{kappa}B activation induced by LPS, okadaic acid, and ceramide. The effect was specific, as the activation of the transcription factor activating protein-1 by TNF was unaffected. Western blot analysis revealed that TNF-dependent degradation of the inhibitory subunit of NF-{kappa}B, I{kappa}B{alpha}, and nuclear translocation of the p65 subunit of NF-{kappa}B were also inhibited. This correlated with suppression of NF-{kappa}B-dependent reporter gene expression induced by TNF. The inhibitory effect of {alpha}-MSH appeared to be mediated through generation of cAMP, as inhibitors of adenylate cyclase and of protein kinase A reversed its inhibitory effect. Similarly, addition of membrane-permeable dibutyryl cAMP, like {alpha}-MSH, suppressed TNF-induced NF-{kappa}B activation. Overall, our results suggest that {alpha}-MSH suppresses NF-{kappa}B activated by various inflammatory agents and that this mechanism probably contributes to its anti-inflammatory effects.




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