Alpha-melanocyte-stimulating hormone reduces impact of proinflammatory cytokine and peroxide-generated oxidative stress on keratinocyte and melanoma cell lines.
We have previously shown that alpha-melanocyte-stimulating hormone (alpha-MSH) can oppose tumor necrosis factor alpha activation of NF-kappaB (1-2 h) and intercellular adhesion molecule 1 up-regulation (mRNA by 3 h and protein by 24 h) in melanocytes and melanoma cells. The present study reports on the ability of four MSH peptides to control intracellular peroxide levels and glutathione peroxidase (GPx) activity in pigmentary and nonpigmentary cells. In human HBL melanoma and HaCaT keratinocytes tumor necrosis factor alpha and H(2)O(2) both activated GPx in a time- and concentration-dependent manner (by 30-45 min). alpha-MSH peptides were found to inhibit the stimulated GPx activity and had biphasic dose-response curves. MSH 1-13 and MSH [Nle(4)-d-Phe(7)] achieved maximum inhibition at 10(-10) and 10(-12) m, respectively. Higher concentrations (10-100 fold) of MSH 4-10 and MSH 11-13 were required to produce equivalent levels of inhibition. alpha-MSH was also capable of reducing peroxide accumulation within 15 min, and again this inhibition was biphasic. The data support a role of alpha-MSH in acute protection of cells to oxidative/cytokine action that precedes NF-kappaB and GPx activation. The rapidity and potency of the response to alpha-MSH in pigmentary and nonpigmentary cells suggest this to be a central role of this peptide in cutaneous cells.
Haycock
J W
JW
University Section of Medicine, Division of Clinical Sciences, Northern General Hospital, Sheffield S5 7AU, United Kingdom. j.w.haycock@shef.ac.uk
Rowe
S J
SJ
Cartledge
S
S
Wyatt
A
A
Ghanem
G
G
Morandini
R
R
Rennie
I G
IG
MacNeil
S
S
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015603:Keratinocytes; D008545:Melanoma; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D010545:Peroxides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000521:alpha-MSH / Q000494:pharmacology*
D016207:Cytokines; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010446:Peptide Fragments; D010545:Peroxides; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D000521:alpha-MSH; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D015056:1-Methyl-3-isobutylxanthine