Alpha-melanocyte-stimulating hormone down-regulates CXC receptors through activation of neutrophil elastase.
Considering the role of interleukin-8 (IL-8) in a large number of acute and chronic inflammatory diseases, the regulation of IL-8-mediated biological responses is important. Alpha-melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide, inhibits most forms of inflammation by an unknown mechanism. In the present study, we have found that alpha-MSH interacts predominantly with melanocortin-1 receptors and inhibits several IL-8-induced biological responses in macrophages and neutrophils. It down-regulated receptors for IL-8 but not for TNF, IL-4, IL-13 or TNF-related apoptosis-inducing ligand (TRAIL) in neutrophils. It down-regulated CXCR type 1 and 2 but not mRNA levels. alpha-MSH did not inhibit IL-8 binding in purified cell membrane or affinity-purified CXCR. IL-8 or anti-CXCR Ab protected against alpha-MSH-mediated inhibition of IL-8 binding. The level of neutrophil elastase, a specific serine protease, but not cathepsin G or proteinase 3 increased in alpha-MSH-treated cells, and restoration of CXCR by specific neutrophil elastase or serine protease inhibitors indicates the involvement of elastase in alpha-MSH-induced down-regulation of CXCR. These studies suggest that alpha-MSH inhibits IL-8-mediated biological responses by down-regulating CXCR through induction of serine protease and that alpha-MSH acts as a potent immunomodulator in neutrophil-driven inflammatory distress.
Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nacharam, Hyderabad, India. manna@cdfd.org.in
Sunil K
SK
Manna
Abira
A
Sarkar
Yashin
Y
Sreenivasan
D000208:Acute Disease; D056649:Cathepsin G; D002403:Cathepsins / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D019272:Leukocyte Elastase / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D053146:Myeloblastin; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D044102:Receptor, Melanocortin, Type 1 / Q000276:immunology* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology*; D012697:Serine Endopeptidases / Q000276:immunology / Q000378:metabolism; D000521:alpha-MSH / Q000276:immunology / Q000494:pharmacology*
D016207:Cytokines; D044102:Receptor, Melanocortin, Type 1; D019707:Receptors, Chemokine; D000521:alpha-MSH; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin