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-Melanocyte-Stimulating Hormone Inhibits the Nuclear Transcription Factor NF-
B Activation Induced by Various Inflammatory Agents
Cytokine Research Laboratory, Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
-Melanocyte-stimulating hormone (
-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-
B, we
investigated the effect of
-MSH on the activation of this
transcription factor by a wide variety of inflammatory stimuli.
Electrophoretic mobility shift assay showed that
-MSH completely
abolished TNF-mediated NF-
B activation in a dose- and time-dependent
manner. It also suppressed NF-
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-
B, I
B
, and nuclear translocation of
the p65 subunit of NF-
B were also inhibited. This correlated with
suppression of NF-
B-dependent reporter gene expression induced by
TNF. The inhibitory effect of
-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
-MSH, suppressed TNF-induced
NF-
B activation. Overall, our results suggest that
-MSH
suppresses NF-
B activated by various inflammatory agents and that
this mechanism probably contributes to its anti-inflammatory
effects.
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