Protective Effects of Melanocortins in Systemic Host Reactions

  • Stefano Gatti
  • Caterina Lonati
  • Andrea Sordi
  • Anna Catania
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 681)

Abstract

Systemic inflammatory reactions are pivotal in many disorders and have important secondary influences in many more. Although inflammation is initially useful to limit infection, it can also be detrimental and cause organ failure. Modulation of systemic reactions is important to restrict mediator release and limit cell activation that could cause harmful consequences. Experiments in which different models and treatments were used show that melanocortins reduce host responses such as fever, shock, reperfusion injury and allograft rejection. Melanocortin-derived peptides could be an effective treatment to prevent organ failure caused by excessive production of pro-inflammatory mediators. The degree of the modulatory effect exerted by melanocortins should be sufficient to reduce severity of systemic inflammation without impairing the host defense mechanisms.

Keywords

Hepatitis Ischemia Pneumonia Interferon Arginine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Dinarello CA. Infection, fever and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res 2004; 10:201–222.PubMedGoogle Scholar
  2. 2.
    Steiner AA, Chakravarty S, Rudaya AY et al. Bacterial lipopolysaccharide fever is initiated via Toll-like receptor 4 on hematopoietic cells. Blood 2006; 107:4000–4002.CrossRefPubMedGoogle Scholar
  3. 3.
    Lipton JM, Glyn JR, Zimmer JA. Hypothermic and antipyretic effects of centrally administered ACTH(1–24) and α-melanotropin. Fed Proc 1981; 40:2760–2762.PubMedGoogle Scholar
  4. 4.
    Tatro JB, Sinha PS. The central melanocortin system and fever. Ann N Y Acad Sci 2003; 994:246–257.CrossRefPubMedGoogle Scholar
  5. 5.
    Davidson J, Milton AS, Rotondo D. Alpha-melanocyte-stimulating hormone suppresses fever and increases in plasma levels of prostaglandin E2 in the rabbit. J Physiol 1992; 451:491–502.PubMedGoogle Scholar
  6. 6.
    . Martin LW, Catania A, Hiltz ME et al. Neuropeptide alpha-MSH antagonizes IL-6-and TNF-induced fever. Peptides 1991; 12:297–299.CrossRefPubMedGoogle Scholar
  7. 7.
    . Martin LW, Deeter LB, Lipton JM. Acute-phase response to endogenous pyrogen in rabbit: effects of age and route of administration. Am J Physiol 1989; 257:R189–193.PubMedGoogle Scholar
  8. 8.
    Shih ST, Lipton JM. Intravenous alpha-MSH reduces fever in the squirrel monkey. Peptides 1985; 6:685–687.CrossRefPubMedGoogle Scholar
  9. 9.
    Holdeman M, Lipton JM. Antipyretic activity of a potent alpha-MSH analog. Peptides 1985; 6:273–275.CrossRefPubMedGoogle Scholar
  10. 10.
    Murphy MT, Lipton JM. Peripheral administration of alpha-MSH reduces fever in older and younger rabbits. Peptides 1982; 3:775–779.CrossRefPubMedGoogle Scholar
  11. 11.
    Murphy MT, Richards DB, Lipton JM. Antipyretic potency of centrally administered alpha-melanocyte stimulating hormone. Science 1983; 221:192–193.CrossRefPubMedGoogle Scholar
  12. 12.
    Catania A, Lipton JM. Peptide modulation of fever and inflammation within the brain. Ann N Y Acad Sci 1998; 856:62–68.CrossRefPubMedGoogle Scholar
  13. 13.
    Glyn JR, Lipton JM. Hypothermic and antipyretic effects of centrally administered ACTH(1-24) and α-melanotropin. Peptides 1981; 2:177–187.CrossRefPubMedGoogle Scholar
  14. 14.
    Richards DB, Lipton JM. Antipyretic doses of α-MSH do not alter afebrile body temperature in the cold. J Thermal Biol 1984; 9:299–301.CrossRefGoogle Scholar
  15. 15.
    Zimmer JA, Lipton JM. Central and peripheral injections of ACTH (1–24) reduce fever in adrenalectomized rabbits. Peptides 1981; 2:419–423.CrossRefPubMedGoogle Scholar
  16. 16.
    Murphy MT, Richards DB, Lipton JM. Antipyretic potency of centrally administered α-melanocyte stimulating hormone. Science 1983; 221:192–193.CrossRefPubMedGoogle Scholar
  17. 17.
    Martin LW, Lipton JM. Acute phase response to endotoxin: rise in plasma α-MSH and effects of a-MSH injection. Am J Physiol 1990; 259:R768–R772.PubMedGoogle Scholar
  18. 18.
    Goelst K, Mitchell D, Laburn H. Effects of alpha-melanocyte stimulating hormone on fever caused by endotoxin in rabbits. J Physiol 1991; 441:469–476.PubMedGoogle Scholar
  19. 19.
    Huang QH, Hruby VJ, Tatro JB. Systemic α-MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release. Am J Physiol 1998; 275:R524–530.PubMedGoogle Scholar
  20. 20.
    Villar M, Perassi N, Celis ME. Central and peripheral actions of α-MSH in the thermoregulation of rats. Peptides 1991; 12:1441–1443.CrossRefPubMedGoogle Scholar
  21. 21.
    Robertson BA, Gahring LC, Daynes RA. Neuropeptide regulation of interleukin-1 activities. Capacity of α-melanocyte stimulating hormone to inhibit interleukin-1 inducible responses in vivo and in vitro exhibits target cell selectivity. Inflammation 1986; 10:371–385.CrossRefPubMedGoogle Scholar
  22. 22.
    Daynes RA, Robertson BA, Cho BH et al. Alpha-melanocyte-stimulating hormone exhibits target cell selectivity in its capacity to affect interleukin 1-inducible responses in vivo and in vitro. J Immunol 1987; 139:103–109.PubMedGoogle Scholar
  23. 23.
    Hori T, Nakashima T, Take S et al. Immune cytokines and regulation of body temperature, food intake and cellular immunity. Brain Res Bull 1991; 27:309–313.CrossRefPubMedGoogle Scholar
  24. 24.
    Richards DB, Lipton JM. Effect of α-MSH(11–13) (lysine-proline-valine) on fever in the rabbit. Peptides 1984; 5:815–817.CrossRefPubMedGoogle Scholar
  25. 25.
    Deeter LB, Martin LW, Lipton JM. Antipyretic properties of centrally administered α-MSH fragments in the rabbit. Peptides 1989; 9:1285–1288.CrossRefGoogle Scholar
  26. 26.
    Samson WK, Lipton JM, Zimmer JA. The effect of fever on central α-MSH concentrations in the rabbit. Peptides 1981; 2:419–423.CrossRefPubMedGoogle Scholar
  27. 27.
    Holdeman M, Khorram O, Samson WK et al. Fever specific changes in MSH and CRF concentrations. Am J Physiol 1985; 248:R125–R129.PubMedGoogle Scholar
  28. 28.
    Bell RC, Lipton JM. Pulsatile release of antipyretic neuropeptide α-MSH from septum of rabbit during fever. Am J Physiol 1987; 252:R1152–R1157.PubMedGoogle Scholar
  29. 29.
    Glyn-Ballinger JR, Bernardini GL, Lipton JM. α-MSH injected into the septal region reduces fever in rabbits. Peptides 1983; 4:199–203.CrossRefPubMedGoogle Scholar
  30. 30.
    Feng JD, Dao T, Lipton JM. Effects of preoptic microinjections of alpha-MSH on fever and normal temperature control in rabbits. Brain Res Bull 1987; 18:473–477.CrossRefPubMedGoogle Scholar
  31. 31.
    Shih ST, Khorram O, Lipton JM et al. Central administration of α-MSH antiserum augments fever in the rabbit. Am J Physiol 1986; 250:R803–R806.PubMedGoogle Scholar
  32. 32.
    Opp MR, Obal F, Kreuger JM. Effects of α-MSH on sleep, behavior and brain temperature: interactions with IL-1. Am J Physiol 1988; 255:R914–R922.PubMedGoogle Scholar
  33. 33.
    Martin SA, Malkinson TJ, Veale WL et al. Depletion of brain α-MSH alters prostaglandin and interleukin fever in rats. Brain Res 1990; 526.Google Scholar
  34. 34.
    Huang QH, Entwistle ML, Alvaro JD et al. Antipyretic role of endogenous melanocortins mediated by central melanocortin receptors during endotoxin-induced fever. J Neurosci 1997; 17:3343–3351.PubMedGoogle Scholar
  35. 35.
    Tatro JB. Endogenous antipyretics. Clin Infect Dis 2000; 31(Suppl)5:S190–201.CrossRefGoogle Scholar
  36. 36.
    van der Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis 2008; 8:32–43.CrossRefPubMedGoogle Scholar
  37. 37.
    Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med 2009; 37:291–304.CrossRefPubMedGoogle Scholar
  38. 38.
    Martin LW, Lipton JM. Acute phase response to endotoxin: rise in plasma alpha-MSH and effects of alpha-MSH injection. Am J Physiol 1990; 259:R768–772.PubMedGoogle Scholar
  39. 39.
    Delgado Hernandez R, Demitri MT, Carlin A et al. Inhibition of systemic inflammation by central action of the neuropeptide alpha-melanocyte-stimulating hormone. Neuroimmunomodulation 1999; 6:187–192.CrossRefPubMedGoogle Scholar
  40. 40.
    Abou-Mohamed G, Papapetropoulos A, Ulrich D et al. HP-228, a novel synthetic peptide, inhibits the induction of nitric oxide synthase in vivo but not in vitro. J Pharmacol Exp Ther 1995; 275:584–591.PubMedGoogle Scholar
  41. 41.
    Lipton JM, Ceriani G, Macaluso A et al. Antiinflammatory effects of the neuropeptide alpha-MSH in acute, chronic and systemic inflammation. Ann N Y Acad Sci 1994; 741:137–148.CrossRefPubMedGoogle Scholar
  42. 42.
    Chiao H, Foster S, Thomas R et al. Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation. J Clin Invest 1996; 97:2038–2044.CrossRefPubMedGoogle Scholar
  43. 43.
    Pepys MB, Rogers SL, Evans DJ. Role of the acute phase response in the Shwartzman phenomenon. Clin Exp Immunol 1982; 47:289–295.PubMedGoogle Scholar
  44. 44.
    Scholzen TE, Sunderkotter C, Kalden DH et al. Alpha-melanocyte stimulating hormone prevents lipopolysaccharide-induced vasculitis by down-regulating endothelial cell adhesion molecule expression. Endocrinology 2003; 144:360–370.CrossRefPubMedGoogle Scholar
  45. 45.
    Capsoni F, Ongari A, Colombo G et al. The synthetic melanocortin (CKPV)2 exerts broad anti-inflammatory effects in human neutrophils. Peptides 2007; 28:2016–2022.CrossRefPubMedGoogle Scholar
  46. 46.
    Gatti S, Carlin A, Sordi A et al. Inhibitory effects of the peptide (CKPV)2 on endotoxin-induced host reactions. J Surg Res 2006; 131:209–214.CrossRefPubMedGoogle Scholar
  47. 47.
    Ichiyama T, Zhao H, Catania A et al. Alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation and IkappaBalpha degradation in human glioma cells and in experimental brain inflammation. Exp Neurol 1999; 157:359–365.CrossRefPubMedGoogle Scholar
  48. 48.
    Haycock JW, Wagner M, Morandini R et al. Alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation in human melanocytes and melanoma cells. J Invest Dermatol 1999; 113:560–566.CrossRefPubMedGoogle Scholar
  49. 49.
    Manna SK, Aggarwal BB. Alpha-melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappa B activation induced by various inflammatory agents. J Immunol 1998; 161:2873–2880.PubMedGoogle Scholar
  50. 50.
    Colombo G, Gatti S, Sordi A et al. Production and effects of alpha-melanocyte-stimulating hormone during acute lung injury. Shock 2007; 27:326–333.CrossRefPubMedGoogle Scholar
  51. 51.
    Shen AS, Haslett C, Feldsien DC et al. The intensity of chronic lung inflammation and fibrosis after bleomycin is directly related to the severity of acute injury. Am Rev Respir Dis 1988; 137:564–571.PubMedGoogle Scholar
  52. 52.
    Matthay MA, Robriquet L, Fang X. Alveolar epithelium: role in lung fluid balance and acute lung injury. Proc Am Thorac Soc 2005; 2:206–213.CrossRefPubMedGoogle Scholar
  53. 53.
    Guarini S, Schioth HB, Mioni C et al. MC(3) receptors are involved in the protective effect of melanocortins in myocardial ischemia/reperfusion-induced arrhythmias. Naunyn Schmiedebergs Arch Pharmacol 2002; 366:177–182.CrossRefPubMedGoogle Scholar
  54. 54.
    Bazzani C, Mioni C, Ferrazza G et al. Involvement of the central nervous system in the protective effect of melanocortins in myocardial ischaemia/reperfusion injury. Resuscitation 2002; 52:109–115.CrossRefPubMedGoogle Scholar
  55. 55.
    . Bazzani C, Guarini S, Botticelli AR et al. Protective effect of melanocortin peptides in rat myocardial ischemia. J Pharmacol Exp Ther 2001; 297:1082–1087.PubMedGoogle Scholar
  56. 56.
    Huh SK, Lipton JM, Batjer HH. The protective effects of alpha-melanocyte stimulating hormone on canine brain stem ischemia. Neurosurgery 1997; 40:132–139; discussion 139–140.CrossRefPubMedGoogle Scholar
  57. 57.
    Huang Q, Tatro JB. Alpha-melanocyte stimulating hormone suppresses intracerebral tumor necrosis factor-alpha and interleukin-1beta gene expression following transient cerebral ischemia in mice. Neurosci Lett 2002; 334:186–190.CrossRefPubMedGoogle Scholar
  58. 58.
    Chiao H, Kohda Y, McLeroy P et al. Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest 1997; 99:1165–1172.CrossRefPubMedGoogle Scholar
  59. 59.
    Kwon TH, Frokiaer J, Han JS et al. Decreased abundance of major Na(+) transporters in kidneys of rats with ischemia-induced acute renal failure. Am J Physiol Renal Physiol 2000; 278:F925–939.PubMedGoogle Scholar
  60. 60.
    Deng J, Kohda Y, Chiao H et al. Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int 2001; 60:2118-2128.Google Scholar
  61. 61.
    Jo SK, Yun SY, Chang KH et al. Alpha-MSH decreases apoptosis in ischaemic acute renal failure in rats: possible mechanism of this beneficial effect. Nephrol Dial Transplant 2001; 16:1583–1591.CrossRefPubMedGoogle Scholar
  62. 62.
    Chiao H, Kohda Y, McLeroy P et al. Alpha-melanocyte-stimulating hormone inhibits renal injury in the absence of neutrophils. Kidney Int 1998; 54:765–774.CrossRefPubMedGoogle Scholar
  63. 63.
    Hassoun HT, Zou L, Moore FA et al. Alpha-melanocyte-stimulating hormone protects against mesenteric ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 2002; 282:G1059–1068.PubMedGoogle Scholar
  64. 64.
    . Lipton JM, Catania A, Ichiyama T. Marshaling the anti-inflammatory influence of the neuroimmunomodulator alpha-MSH. News Physiol Sci 2000; 15:192–195.PubMedGoogle Scholar
  65. 65.
    Kwon TH, Frokiaer J, Fernandez-Llama P et al. Reduced abundance of aquaporins in rats with bilateral ischemia-induced acute renal failure: prevention by alpha-MSH. Am J Physiol 1999; 277:F413–427.PubMedGoogle Scholar
  66. 66.
    Pascual M, Swinford RD, Ingelfinger JR et al. Chronic rejection and chronic cyclosporin toxicity in renal allografts. Immunol Today 1998; 19:514–519.CrossRefPubMedGoogle Scholar
  67. 67.
    Dallman MJ. Immunobiology of graft rejection. In: Ginns LC, Cosimi AB, Morris PJ, eds. Transplantation. Malden, MA: Blackwell Science, 1999;23–35.Google Scholar
  68. 68.
    Gatti S, Colombo G, Buffa R et al. Alpha-melanocyte-stimulating hormone protects the allograft in experimental heart transplantation. Transplantation 2002; 74:1678–1684.CrossRefPubMedGoogle Scholar
  69. 69.
    Colombo G, Gatti S, Turcatti F et al. Gene expression profiling reveals multiple protective influences of the peptide α-melanocyte-stimulating hormone in experimental heart transplantation. J Immunol 2005; 175:3391–3401.PubMedGoogle Scholar
  70. 70.
    Colombo G, Sordi A, Lonati C et al. Treatment with alpha-melanocyte stimulating hormone preserves calcium regulatory proteins in rat heart allografts. Brain Behav Immun 2008; 22:817–823.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Stefano Gatti
    • 1
  • Caterina Lonati
    • 2
  • Andrea Sordi
    • 2
  • Anna Catania
    • 2
  1. 1.Centro di Ricerche Chirurgiche PreclinicheFondazione IRCCSMilanoItaly
  2. 2.Center for Preclinical InvestigationFondazione IRCCS Ca’ GrandaMilanoItaly

Personalised recommendations