Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases.
Alpha-MSH is a tridecapeptide derived from proopiomelanocortin. Many studies over the last few years have provided evidence that alpha-MSH has potent protective and antiinflammatory effects. These effects can be elicited via centrally expressed melanocortin receptors that orchestrate descending neurogenic antiinflammatory pathways. alpha-MSH can also exert antiinflammatory and protective effects on cells of the immune system and on peripheral nonimmune cell types expressing melanocortin receptors. At the molecular level, alpha-MSH affects various pathways implicated in regulation of inflammation and protection, i.e., nuclear factor-kappaB activation, expression of adhesion molecules and chemokine receptors, production of proinflammatory cytokines and mediators, IL-10 synthesis, T cell proliferation and activity, inflammatory cell migration, expression of antioxidative enzymes, and apoptosis. The antiinflammatory effects of alpha-MSH have been validated in animal models of experimentally induced fever; irritant and allergic contact dermatitis, vasculitis, and fibrosis; ocular, gastrointestinal, brain, and allergic airway inflammation; and arthritis, but also in models of organ injury. One obstacle limiting the use of alpha-MSH in inflammatory disorders is its pigmentary effect. Due to its preserved antiinflammatory effect but lack of pigmentary action, the C-terminal tripeptide of alpha-MSH, KPV, has been delineated as an alternative for antiinflammatory therapy. KdPT, a derivative of KPV corresponding to amino acids 193-195 of IL-1beta, is also emerging as a tripeptide with antiinflammatory effects. The physiochemical properties and expected low costs of production render both agents suitable for the future treatment of immune-mediated inflammatory skin and bowel disease, fibrosis, allergic and inflammatory lung disease, ocular inflammation, and arthritis.
Brzoska
Thomas
T
Department of Dermatology, University of Münster, Von Esmarch-Strasse 58, D-48149 Münster, Germany.
Luger
Thomas A
TA
Maaser
Christian
C
Abels
Christoph
C
Böhm
Markus
M
D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D008969:Molecular Sequence Data; D010455:Peptides / Q000627:therapeutic use; D000521:alpha-MSH / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D010455:Peptides; D000521:alpha-MSH