Regulation of NF-kappaB activation by protein phosphatase 2B and NO, via protein kinase A activity, in human monocytes

It has been reported previously that a short synthetic immunomodulating peptide (Pa) and the neuropeptide beta-endorphin modulate the immune system. We have found now that NF-kappaB participates in the stimulation of monocytes by both peptides and we investigated the molecular mechanism by which the...

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Bibliographic Details
Published in:Nitric oxide 2003-02, Vol.8 (1), p.65-74
Main Authors: Bengoechea-Alonso, M Teresa, Pelacho, Beatriz, Osés-Prieto, Juan A, Santiago, Esteban, López-Moratalla, Natalia, López-Zabalza, María J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
beta-Endorphin - pharmacology
Blotting, Western
Calcineurin - metabolism
Cells, Cultured
Cyclic AMP-Dependent Protein Kinases - metabolism
Enzyme Activation
GTP-Binding Protein alpha Subunits, Gs - metabolism
Humans
Molecular Sequence Data
Monocytes - enzymology
Monocytes - metabolism
NF-kappa B - metabolism
Nitrates - metabolism
Nitric Oxide - metabolism
Protein Subunits - metabolism
Signal Transduction - drug effects
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Summary:It has been reported previously that a short synthetic immunomodulating peptide (Pa) and the neuropeptide beta-endorphin modulate the immune system. We have found now that NF-kappaB participates in the stimulation of monocytes by both peptides and we investigated the molecular mechanism by which these stimuli activate NF-kappaB. Pa and beta-endorphin induce accumulation of cyclic 3('),5(')-adenosine monophosphate (cAMP) in a calcium/calmodulin-dependent fashion since it was completely inhibited by the calmodulin antagonist W-7. The effect of these complexes seems to be mediated, at least in part, by nitric oxide (NO) synthesized by constitutive NO synthase since the NO synthase inhibitor N-methyl-L-arginine (NMLA) reduced the elevation of cAMP. Furthermore, the NO donor SIN-1 provoked nitration of G(S)alpha, leading to the cAMP elevation that was suppressed by the G(S)alpha-selective antagonist NF-449. Interestingly, the rapid degradation of NF-kappaB inhibitor IkappaBalpha induced by Pa- and beta-endorphin was reversed by a pretreatment with H-89 and cyclosporin A, inhibitors of protein kinase A (PKA) and protein phosphatase 2B (PP2B), respectively. These observations are consistent with the inhibition caused by W-7, NMLA, H-89, and cyclosporin A on NF-kappaB induction by these agonists, indicating the involvement of PKA and PP2B in the regulation of NF-kappaB in human monocytes.
ISSN:1089-8603