α-Melanocyte-stimulating Hormone Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α Production in Leukocytes by Modulating Protein Kinase A, p38 Kinase, and Nuclear Factor κB Signaling Pathways

Abstract

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) inhibits inflammation by down-regulating the expression of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) in leukocytes via stimulation of α-MSH cell surface receptors. However, the signaling mechanism of α-MSH action has not yet been clearly elucidated. Here, we have investigated signaling pathways by which α-MSH inhibits lipopolysaccharide (LPS)-induced TNF-α production in leukocytes such as THP-1 cells. We focused on the possible roles of protein kinase A (PKA), p38 kinase, and nuclear factor κB (NFκB) signaling. In THP-1 cells, LPS is known to activate p38 kinase, which in turn activates NFκB to induce TNF-α production. We found that pretreatment of cells with α-MSH blocked LPS-induced p38 kinase and NFκB activation as well as TNF-α production. This response was proportional to α-MSH receptor expression levels, and addition of an α-MSH receptor antagonist abolished the inhibitory effects. In addition, α-MSH treatment activated PKA, and PKA inhibition abrogated the inhibitory effects of α-MSH on p38 kinase activation, NFκB activation, and TNF-α production. Taken together, our results indicate that stimulation of PKA by α-MSH causes inhibition of LPS-induced activation of p38 kinase and NFκB to block TNF-α production. The neuropeptide α-melanocyte-stimulating hormone (α-MSH) inhibits inflammation by down-regulating the expression of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) in leukocytes via stimulation of α-MSH cell surface receptors. However, the signaling mechanism of α-MSH action has not yet been clearly elucidated. Here, we have investigated signaling pathways by which α-MSH inhibits lipopolysaccharide (LPS)-induced TNF-α production in leukocytes such as THP-1 cells. We focused on the possible roles of protein kinase A (PKA), p38 kinase, and nuclear factor κB (NFκB) signaling. In THP-1 cells, LPS is known to activate p38 kinase, which in turn activates NFκB to induce TNF-α production. We found that pretreatment of cells with α-MSH blocked LPS-induced p38 kinase and NFκB activation as well as TNF-α production. This response was proportional to α-MSH receptor expression levels, and addition of an α-MSH receptor antagonist abolished the inhibitory effects. In addition, α-MSH treatment activated PKA, and PKA inhibition abrogated the inhibitory effects of α-MSH on p38 kinase activation, NFκB activation, and TNF-α production. Taken together, our results indicate that stimulation of PKA by α-MSH causes inhibition of LPS-induced activation of p38 kinase and NFκB to block TNF-α production. The α-melanocyte-stimulating hormone (α-MSH) 1The abbreviations used are: α-MSH, α-melanocyte-stimulating hormone; ERK, extracellular signal-regulated protein kinase; IκB, inhibitory κB; IKK, IκB kinase; LPS, lipopolysaccharide; MAP, mitogen-activated protein; MAPK, MAP kinase; MEK, MAPK/ERK kinase; MEKK, MEK kinase; MCR, melanocortin receptors; NFκB, nuclear factor κB; PKA, protein kinase A; PMA, phorbol myristate acetate; TNF-α, tumor necrosis factor-α.1The abbreviations used are: α-MSH, α-melanocyte-stimulating hormone; ERK, extracellular signal-regulated protein kinase; IκB, inhibitory κB; IKK, IκB kinase; LPS, lipopolysaccharide; MAP, mitogen-activated protein; MAPK, MAP kinase; MEK, MAPK/ERK kinase; MEKK, MEK kinase; MCR, melanocortin receptors; NFκB, nuclear factor κB; PKA, protein kinase A; PMA, phorbol myristate acetate; TNF-α, tumor necrosis factor-α. is a 13-amino-acid-long neuropeptide produced by intracellular cleavage of the proopiomelanocortin hormone. α-MSH mediates the communication between the nervous and immune systems (1Catania A. Lipton J.M. Neuroimmunomodulation. 1994; 1: 93-99Crossref PubMed Scopus (42) Google Scholar, 2Chambers D.A. Schauenstein K. Immunol. Today. 2000; 21: 168-170Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar) and is expressed in pituitary cells, neurons, keratinocytes, and macrophages, where it regulates neurological, endocrine, and immune activities (1Catania A. Lipton J.M. Neuroimmunomodulation. 1994; 1: 93-99Crossref PubMed Scopus (42) Google Scholar, 3Catania A. Lipton J.M. Ann. N. Y. Acad. Sci. 1993; 680: 412-423Crossref PubMed Scopus (30) Google Scholar, 4Catania A. Gerloni V. Procaccia S. Airaghi L. Manfredi M.G. Lomater C. Grossi L. Lipton J.M. Neuroimmunomodulation. 1994; 1: 321-328Crossref PubMed Scopus (53) Google Scholar, 5Lipton J.M. Catania A. Ann. N. Y. Acad. Sci. 1998; 840: 373-380Crossref PubMed Scopus (66) Google Scholar, 6Ichiyama T. Sakai T. Catania A. Barsh G.S. Furukawa S. Lipton J.M. J. Neuroimmunol. 1999; 99: 211-217Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The anti-inflammatory activity of α-MSH has been demonstrated in various disease models including arthritis, septic shock induced by hepatic injury, and endotoxemia/ischemia, suggesting that α-MSH is a promising candidate therapeutic drug for inflammatory diseases (7Chiao H. Foster S. Thomas R. Lipton J. Star R.A. J. Clin. Invest. 1996; 97: 2038-2044Crossref PubMed Scopus (128) Google Scholar, 8Oktar B.K. Ercan F. Yegen B.C. Alican I. Peptides (Elmsford). 2000; 21: 1271-1277Crossref PubMed Scopus (33) Google Scholar, 9Rajora N. Boccoli G. Catania A. Lipton J.M. Peptides (Elmsford). 1997; 18: 381-385Crossref PubMed Scopus (96) Google Scholar, 10Airaghi L. Lettino M. Manfredi M.G. Lipton J.M. Catania A. Am. Heart J. 1995; 130: 204-211Crossref PubMed Scopus (44) Google Scholar). The anti-inflammatory effects of α-MSH involve a reduction in expression of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interferon-γ, and interleukin-1, -6, and -8, and inhibition of the inflammatory actions of leukocytes such as neutrophils and macrophages (9Rajora N. Boccoli G. Catania A. Lipton J.M. Peptides (Elmsford). 1997; 18: 381-385Crossref PubMed Scopus (96) Google Scholar, 11Cannon J.G. Tatro J.B. Reichlin S. Dinarello C.A. J. Immunol. 1986; 137: 2232-2236PubMed Google Scholar, 12Rajora N. Boccoli G. Burns D. Sharma S. Catania A.P. Lipton J.M. J. Neurosci. 1997; 17: 2181-2186Crossref PubMed Google Scholar, 13Bohm M. Schulte U. Kalden H. Luger T.A. Ann. N. Y. Acad. Sci. 1999; 885: 277-286Crossref PubMed Scopus (59) Google Scholar). In addition, it has been shown that the anti-inflammatory action of α-MSH is due to its ability to block proinflammatory signaling such as activation of nuclear factor κB (NFκB) (13Bohm M. Schulte U. Kalden H. Luger T.A. Ann. N. Y. Acad. Sci. 1999; 885: 277-286Crossref PubMed Scopus (59) Google Scholar, 14Ichiyama T. Zhao H. Catania A. Furukawa S. Lipton J.M. Exp. Neurol. 1999; 157: 359-365Crossref PubMed Scopus (83) Google Scholar). α-MSH exerts its cellular effects by binding to five different G protein-coupled receptors called melanocortin receptors (MC1R_ MC5R) (15Getting S.J. Trends Pharmacol. Sci. 2002; 23: 447-449Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 16Rajora N. Ceriani G. Catania A. Star R.A. Murphy M.T. Lipton J.M. J. Leukocyte Biol. 1996; 59: 248-253Crossref PubMed Scopus (152) Google Scholar, 17Mountjoy K.G. Robbins L.S. Mortrud M.T. Cone R.D. Science. 1992; 257: 1248-1251Crossref PubMed Scopus (1443) Google Scholar, 18Gantz I. Konda Y. Tashiro T. Shimoto Y. Miwa H. Munzert G. Watson S.J. DelValle J. Yamada T. J. Biol. Chem. 1993; 268: 8246-8250Abstract Full Text PDF PubMed Google Scholar). Ligand binding to MCRs activates adenyl cyclase, which leads to the production of cAMP and subsequent activation of protein kinase A (PKA) (15Getting S.J. Trends Pharmacol. Sci. 2002; 23: 447-449Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 19Taherzadeh S. Sharma S. Chhajlani V. Gantz I. Rajora N. Demitri M.T. Kelly L. Zhao H. Ichiyama T. Catania A. Lipton J.M. Am. J. Physiol. 1999; 276: R1289-R1294PubMed Google Scholar, 20Catania A. Rajora N. Capsoni F. Minonzio F. Star R.A. Lipton J.M. Peptides (Elmsford). 1996; 17: 675-679Crossref PubMed Scopus (182) Google Scholar). MC1R, which is expressed on the surface of leukocytes, is thought to be the major receptor mediating the anti-inflammatory activity of α-MSH (19Taherzadeh S. Sharma S. Chhajlani V. Gantz I. Rajora N. Demitri M.T. Kelly L. Zhao H. Ichiyama T. Catania A. Lipton J.M. Am. J. Physiol. 1999; 276: R1289-R1294PubMed Google Scholar, 20Catania A. Rajora N. Capsoni F. Minonzio F. Star R.A. Lipton J.M. Peptides (Elmsford). 1996; 17: 675-679Crossref PubMed Scopus (182) Google Scholar). However, the molecular mechanism of intracellular signal transduction leading to the anti-inflammatory action of α-MSH is not yet clearly understood. Lipopolysaccharide (LPS) is a major inflammatory molecule that triggers the production of proinflammatory cytokines such as TNF-α in various cell types (21Guha M. Mackman N. Cell. Signal. 2001; 13: 85-94Crossref PubMed Scopus (1934) Google Scholar, 22Hawiger J. Immunol. Res. 2001; 23: 99-109Crossref PubMed Google Scholar). In monocytes and macrophages, LPS is known to stimulate TNF-α production by activating mitogen-activated protein (MAP) kinase subtypes including extracellular signal-regulated kinase (ERK), p38 kinase, and c-Jun N-terminal kinase (23White J.E. Lin H.Y. Davis F.B. Davis P.J. Tsan M.F. J. Cell. Physiol. 2000; 182: 381-389Crossref PubMed Scopus (17) Google Scholar, 24Mancuso G. Midiri A. Beninati C. Piraino G. Valenti A. Nicocia G. Teti D. Cook J. Teti G. J. Immunol. 2002; 169: 1401-1409Crossref PubMed Scopus (68) Google Scholar, 25MacKenzie S. Fernandez-Troy N. Espel E. J. Leukocyte Biol. 2002; 71: 1026-1032PubMed Google Scholar). Among the MAP kinase subtypes, specific inhibitors for p38 kinase have been shown to inhibit LPS-induced TNF-α production (26Salituro F.G. Germann U.A. Wilson K.P. Bemis G.W. Fox T. Su M.S. Curr. Med. Chem. 1999; 6: 807-823PubMed Google Scholar, 27Rutault K. Hazzalin C.A. Mahadevan L.C. J. Biol. Chem. 2001; 276: 6666-6674Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 28Nick J.A. Young S.K. Arndt P.G. Lieber J.G. Suratt B.T. Poch K.R. Avdi N.J. Malcolm K.C. Taube C. Henson P.M. Worthen G.S. J. Immunol. 2002; 169: 5260-5269Crossref PubMed Scopus (100) Google Scholar). In addition, α-MSH is known to block LPS-induced expression of TNF-α (19Taherzadeh S. Sharma S. Chhajlani V. Gantz I. Rajora N. Demitri M.T. Kelly L. Zhao H. Ichiyama T. Catania A. Lipton J.M. Am. J. Physiol. 1999; 276: R1289-R1294PubMed Google Scholar), and the inhibitory effects of α-MSH are mediated by the inhibition of NFκB, which stimulates TNF-α production at the transcriptional level (29Luger T.A. Brzoska T. Scholzen T.E. Kalden D.H. Sunderkotter C. Armstrong C. Ansel J. Ann. N. Y. Acad. Sci. 2000; 917: 232-238Crossref PubMed Scopus (76) Google Scholar, 30Mandrika I. Muceniece R. Wikberg J.E. Biochem. Pharmacol. 2001; 61: 613-621Crossref PubMed Scopus (74) Google Scholar). Although the signaling pathway by which α-MSH blocks TNF-α production is not clearly understood, the above observations suggest the possibility that α-MSH blocks LPS-induced TNF-α production by modulating MAP kinase and NFκB activation. Accordingly, we have investigated the functional relationships among PKA, p38 kinase, and NFκB in the antiinflammatory action of α-MSH within inflammatory leukocytes (i.e. macrophages and neutrophils). For this purpose, we treated THP-1 and HL-60 cells with phorbol myristate acetate (PMA) or Me2SO, which induces differentiation into macrophages and neutrophils, respectively. Using these cells, we found that activation of PKA by α-MSH inhibits LPS-induced TNF-α production in differentiated THP-1 cells by inhibiting LPS-induced activation of p38 kinase and subsequent NFκB activation to block TNF-α production. However, the differentiated HL-60 cells expressing lower expression of MC1R did not show the significant effect of α-MSH on the activation of p38 kinase and NFκB. To our knowledge, this would appear to be the first report to show that p38 kinase is a major signaling molecule that transduces α-MSH-mediated anti-inflammatory intracellular signal to the nucleus by inhibiting the NF-κB activation and TNF-α production. Reagents—The anti-MC1R antibody was obtained from Research Diagnostic Inc. (Flanders, NJ). The horseradish peroxidase-conjugated goat anti-mouse monoclonal antibody was purchased from Bio-Rad. Rabbit anti-phospho p38 kinase and anti-p38 kinase polyclonal antibody, mouse anti-phospho monoclonal antibody, anti-phospho polyclonal antibody, and horseradish peroxidase-conjugated goat polyclonal antibody purchased from Rabbit polyclonal antibody and LPS purchased from p38 kinase and PKA purchased from Rabbit polyclonal IκB kinase and purchased from and PKA purchased from The α-MSH and purchased from cells in with treated with for to induce differentiation into neutrophils S.J. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). THP-1 cells in with and treated with for to induce differentiation into macrophages K. N. Y. J. Immunol. 1998; Google Scholar). The differentiated neutrophils and macrophages treated with LPS to induce TNF-α production in the and of various as was from differentiated HL-60 and THP-1 cells the to the The of to was with TNF-α of of for for for MC1R of of for for and for of of for for and for HL-60 and THP-1 cells in a and in of protein in a and a The was blocked with in and with the The a peroxidase-conjugated antibody and an NFκB activity was by differentiated THP-1 cells with a a and response or a The cells in for and or treated with various as in and activity was by a from activity was cell in and inhibitors and and inhibitors and The cell with antibody protein for and THP-1 cells and was as activity was by immune in of kinase and kinase for at by and of expressed as a The by and by PKA activity was by the of to a the PKA the kinase was by of with to of at for the was by of of the was to a and PKA activity was an α-MSH LPS-induced TNF-α in THP-1 first investigated α-MSH receptor expression in HL-60 and THP-1 cells, cells that been to into macrophages and neutrophils, respectively. specific to MC1R the The expression of MC1R in differentiated THP-1 cells in differentiated HL-60 cells The expression of MC1R protein by that THP-1 cells expressed MC1R did HL-60 cells with the observations by S. Fernandez-Troy N. Espel E. J. Leukocyte Biol. 2002; 71: 1026-1032PubMed Google Scholar, A. K. H. K. K. M. S. Biochem. Res. 2001; PubMed Scopus Google Scholar), LPS treatment TNF-α production in THP-1 cells and HL-60 cells. To the of α-MSH in LPS-induced TNF-α we cells with α-MSH for to stimulation with shown in α-MSH treatment LPS-induced TNF-α production in THP-1 cells. However, α-MSH did not LPS-induced TNF-α production in HL-60 cells suggesting that the ability of α-MSH to block LPS-induced TNF-α production is on the of its receptor α-MSH LPS-induced TNF-α by p38 is known to stimulate TNF-α production in monocytes and macrophages by activating MAP kinase signaling (21Guha M. Mackman N. Cell. Signal. 2001; 13: 85-94Crossref PubMed Scopus (1934) Google Scholar, 27Rutault K. Hazzalin C.A. Mahadevan L.C. J. Biol. Chem. 2001; 276: 6666-6674Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, M. K. A. Foster M.G. J. Pharmacol. 2001; PubMed Scopus Google Scholar). we α-MSH inhibits LPS-induced TNF-α production by modulating LPS-induced p38 kinase activation. that LPS treatment activated p38 kinase in differentiated THP-1 cells and HL-60 cells of cells with α-MSH to LPS stimulation the of activated p38 kinase in THP-1 cells not in HL-60 cells This that the ability of α-MSH to block LPS-induced p38 kinase activity is proportional to the of its receptor which is with the of We the of the inhibition of LPS-induced p38 kinase activation by α-MSH in TNF-α production by a p38 shown in α-MSH LPS-induced p38 kinase activation and in THP-1 cells in a In addition, inhibition of LPS-induced p38 kinase activation with specific blocked LPS-induced p38 kinase activation and TNF-α production in a The results from and The that the kinase to and of the level with LPS by α-MSH and The results suggest that the inhibition of p38 kinase by α-MSH to the inhibition of LPS-induced TNF-α production in THP-1 of p38 kinase activation by α-MSH causes the of TNF-α production. THP-1 cells with the of α-MSH for or for and with LPS for of p38 and p38 kinase by of in A and the The used to the of The of protein is expressed as the of that in the of LPS the in the of LPS for TNF-α and by in THP-1 cells with the of α-MSH for or for and with LPS for The a from molecular α-MSH LPS-induced NFκB via p38 α-MSH is known to inhibit activation of NFκB (13Bohm M. Schulte U. Kalden H. Luger T.A. Ann. N. Y. Acad. Sci. 1999; 885: 277-286Crossref PubMed Scopus (59) Google Scholar, 14Ichiyama T. Zhao H. Catania A. Furukawa S. Lipton J.M. Exp. Neurol. 1999; 157: 359-365Crossref PubMed Scopus (83) Google Scholar), we investigated α-MSH inhibits LPS-induced NFκB activation and is a functional between p38 kinase and NFκB activation. NFκB activation was by of IκB of IκB via its is for nuclear of NFκB and subsequent activation of In THP-1 cells, LPS treatment activation of NFκB as demonstrated by the of IκB and NFκB the level of the protein as the level of the protein of α-MSH that inhibits LPS-induced p38 kinase activation or inhibition of p38 kinase with blocked LPS-induced IκB and LPS-induced IκB and lower and transcriptional activity of NFκB suggesting that inhibition of LPS-induced p38 kinase activation by α-MSH is for the inhibition of NFκB. The to and of the level with LPS by α-MSH and The ability of α-MSH to inhibit to its ability to inhibit as α-MSH inhibits the LPS-induced activity In to the inhibition of NFκB by the of p38 kinase activation, inhibition of NFκB activation by treatment with which blocks NFκB activation by inhibiting nuclear of NFκB N. T. R. V. Biochem. Res. 2001; PubMed Scopus Google Scholar, C. M. B.K. Biol. 2002; PubMed Scopus Google Scholar), did not p38 kinase activation did inhibit LPS-induced TNF-α production Taken together, these results suggest that LPS-induced p38 kinase activation is for NFκB activation and that α-MSH inhibits TNF-α production by LPS-induced p38 kinase activation and subsequent NFκB blocks TNF-α production by inhibiting NFκB activation. THP-1 cells or treated with α-MSH for or with for and with LPS for of p38 and p38 kinase by for TNF-α and by The a from molecular was found that the THP-1 cells expressed and in addition to the MC1R the HL-60 cells expressed the MC1R receptor this is with the report by (19Taherzadeh S. Sharma S. Chhajlani V. Gantz I. Rajora N. Demitri M.T. Kelly L. Zhao H. Ichiyama T. Catania A. Lipton J.M. Am. J. Physiol. 1999; 276: R1289-R1294PubMed Google Scholar), found that THP-1 cells MC1R, and MC1R and and yet not are known to be with the anti-inflammatory effect of α-MSH (15Getting S.J. Trends Pharmacol. Sci. 2002; 23: 447-449Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 30Mandrika I. Muceniece R. Wikberg J.E. Biochem. Pharmacol. 2001; 61: 613-621Crossref PubMed Scopus (74) Google Scholar), the expression level of in THP-1 cells and to α-MSH are lower for MC1R and J.E. Muceniece R. I. J. C. A. Pharmacol. Res. 2000; PubMed Scopus Google Scholar), the receptor was investigated which is a antagonist of α-MSH and which is a specific antagonist of the differentiated THP-1 cells with the inhibitory effects of α-MSH on LPS-induced p38 kinase activation and on the effects of α-MSH and Accordingly, these the that MC1R is the major α-MSH receptor that mediates the inhibitory effect of α-MSH on the LPS-induced activation of p38 kinase and NFκB, leading to a TNF-α production in differentiated THP-1 cells. of PKA for the of α-MSH on p38 and α-MSH binding to MC1R is known to activate the PKA signaling pathway (15Getting S.J. Trends Pharmacol. Sci. 2002; 23: 447-449Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 19Taherzadeh S. Sharma S. Chhajlani V. Gantz I. Rajora N. Demitri M.T. Kelly L. Zhao H. Ichiyama T. Catania A. Lipton J.M. Am. J. Physiol. 1999; 276: R1289-R1294PubMed Google Scholar, 20Catania A. Rajora N. Capsoni F. Minonzio F. Star R.A. Lipton J.M. Peptides (Elmsford). 1996; 17: 675-679Crossref PubMed Scopus (182) Google Scholar), we the functional between PKA activation and α-MSH inhibition of p38 kinase and NFκB. α-MSH PKA activity in THP-1 cells. The addition of LPS did not PKA activation, addition of the blocked PKA activation The inhibition of PKA activation by treatment blocked the inhibition of LPS-induced activation of p38 kinase, IκB and IκB as well as TNF-α production results clearly indicate that stimulation of PKA by α-MSH causes inhibition of LPS-induced activation of p38 kinase and subsequent NFκB activation to block TNF-α production. α-MSH is known to inflammation by inhibiting expression of inflammatory cytokines, including TNF-α in leukocytes by inhibiting NF-κB activation J.M. Zhao H. Ichiyama T. Barsh G.S. Catania A. Ann. N. Y. Acad. Sci. 1999; 885: PubMed Scopus Google Scholar). However, the molecular of these α-MSH anti-inflammatory effects have not been MC1R is expressed in monocytes and of and an in the anti-inflammatory action of α-MSH (19Taherzadeh S. Sharma S. Chhajlani V. Gantz I. Rajora N. Demitri M.T. Kelly L. Zhao H. Ichiyama T. Catania A. Lipton J.M. Am. J. Physiol. 1999; 276: R1289-R1294PubMed Google Scholar, G. I. R. Muceniece R. L. Wikberg J.E. Clin. Exp. Immunol. 2001; PubMed Scopus Google Scholar). Here, we found that THP-1 cells MC1R with HL-60 cells. differentiated THP-1 MC1R and HL-60 MC1R we demonstrated that α-MSH blocks LPS-induced TNF-α production by inhibiting LPS-induced activation of p38 kinase and subsequent NFκB activation in a on MC1R We demonstrated that the inhibitory effects of α-MSH activation of MC1R and are known to be with the anti-inflammatory effect of α-MSH (15Getting S.J. Trends Pharmacol. Sci. 2002; 23: 447-449Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 30Mandrika I. Muceniece R. Wikberg J.E. Biochem. Pharmacol. 2001; 61: 613-621Crossref PubMed Scopus (74) Google Scholar) and THP-1 cells we the effects of α-MSH antagonist of α-MSH and antagonist of on the activation of p38 kinase and the of We found that the anti-inflammatory effects of α-MSH in MC1R cells and that these effects abolished by the addition of not by that of observations suggest that MC1R expression is for the inhibitory action of α-MSH in differentiated THP-1 cells. and have that a effect of α-MSH is of activation of NFκB J.M. Zhao H. Ichiyama T. Barsh G.S. Catania A. Ann. N. Y. Acad. Sci. 1999; 885: PubMed Scopus Google Scholar). with this is our that the ability of α-MSH to inhibit TNF-α production is due to the of LPS-induced NFκB activation. The ability of α-MSH to inhibit NFκB activation to be in that it inhibition of This is on the that α-MSH inhibits LPS-induced leading to We that α-MSH inhibits and NFκB activation not as has been by S.K. J. Immunol. 1998; Google Scholar). We found that the inhibition of NFκB by α-MSH is due to inhibition of the signaling molecule p38 This is with observations by that LPS stimulates p38 kinase in various cell types C. L. M. J. 2001; PubMed Scopus Google Scholar, T. H. J. H. Murphy Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar) and that p38 kinase activation by various extracellular leads to the activation of NFκB Pharmacol. 1999; PubMed Scopus Google Scholar, D. A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). we found that the α-MSH for inhibition of p38 kinase activation and subsequent NFκB activation our was we found that of α-MSH in p38 kinase activation This inhibitory effect of α-MSH on p38 kinase is with the that α-MSH is at a and that its anti-inflammatory effects are in of A. Rajora N. Capsoni F. Minonzio F. Star R.A. Lipton J.M. Peptides (Elmsford). 1996; 17: 675-679Crossref PubMed Scopus (182) Google Scholar, S.J. S. A. G. R. S. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of MC1R activates adenyl cyclase, leading to the production of cAMP and subsequent activation of PKA (15Getting S.J. Trends Pharmacol. Sci. 2002; 23: 447-449Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 19Taherzadeh S. Sharma S. Chhajlani V. Gantz I. Rajora N. Demitri M.T. Kelly L. Zhao H. Ichiyama T. Catania A. Lipton J.M. Am. J. Physiol. 1999; 276: R1289-R1294PubMed Google Scholar, 20Catania A. Rajora N. Capsoni F. Minonzio F. Star R.A. Lipton J.M. Peptides (Elmsford). 1996; 17: 675-679Crossref PubMed Scopus (182) Google Scholar). results indicate that the inhibitory effects of α-MSH on LPS-induced activation of p38 kinase and NFκB are mediated by the activation of PKA via the stimulation of the MC1R This is on the that inhibition of PKA with blocks the inhibitory effects of α-MSH on the inhibition of p38 kinase activation and TNF-α production of PKA on NFκB activation has been H. H. H. S. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and this in with our that it would be to the leading to the inhibition of p38 kinase by the activation of possibility is that the inhibition is mediated inhibition of by PKA C. H. H. Cell. Biol. 2002; PubMed Scopus Google Scholar) is to induce the activation of NFκB MAP kinase kinase kinase which induces MAP kinase kinase and p38 kinase activation D. A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. A. T. Acad. Sci. U. S. A. 2000; 97: PubMed Scopus (152) Google Scholar). I. Muceniece R. Wikberg J.E. Biochem. Pharmacol. 2001; 61: 613-621Crossref PubMed Scopus (74) Google Scholar) that inhibition of PKA by blocks the inhibitory effects of α-MSH on production and NFκB activation by that it not NFκB to the nucleus in mouse This that α-MSH via and the on activation. In this we demonstrated that PKA activity is for the of LPS-induced activation of p38 kinase and subsequent NFκB activation and TNF-α production. the α-MSH inhibition of p38 kinase activation in THP-1 a The demonstrated that the LPS-induced activation of p38 kinase was by α-MSH treatment and that the activity was leading to a in the and of and the inhibition of NFκB activation. was that p38 kinase inhibitors be used for the therapeutic drug for diseases (26Salituro F.G. Germann U.A. Wilson K.P. Bemis G.W. Fox T. Su M.S. Curr. Med. Chem. 1999; 6: 807-823PubMed Google Scholar). our results that the p38 kinase in LPS-induced monocytes treated with α-MSH or the p38 kinase induces the inhibition of IKK, NFκB activation, and TNF-α the of α-MSH as a therapeutic drug for inflammatory diseases by as a p38 kinase be We for the anti-phospho and Research of and for

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