title: Neuropeptide alpha-MSH exerts pro-inflammatory effects on Neisseria meningitidis infection in vitro.
abstract: OBJECTIVE
  alpha-Melanoycte stimulating hormone (alpha-MSH), a neuropeptide hormone with reported anti-microbial and immuno-modulatory properties in vitro, has previously been detected in the cerebrospinal fluid of children with bacterial meningitis. We investigated the therapeutic effects of alpha-MSH administration on Neisseria meningitidis infection of human meningeal cell cultures in vitro.
  
  
  METHODS
  Meningeal cell lines (n = 2) were infected with meningococci (10(2)-10(8) cfu/monolayer), isolated bacterial outer membranes (OM; 1 microg/ml) or lipo-oligosaccharide (LOS; 1 microg/ml) with and without alpha-MSH (10(-5)-10 microM). Bacterial adherence was quantified at 6 h, and cytokine production and microbicidal activity of alpha-MSH for meningococci were assessed at 24 h.
  
  
  RESULTS
  Compared with infection by meningococci alone, alpha-MSH (10 microM) up-regulated secretion of IL-6 and IL-8 (mean values increased from approximately 33 to 60 ng/ml), RANTES (mean values increased from approximately 26 to 105 ng/ml) and GM-CSF (mean values increased from approximately 0.3 to 1 ng/ml; P < 0.05). Upregulated secretion correlated with a neuropeptide-mediated rapid and >5-fold increase (P < 0.05) in bacterial adherence to cells and was dependent on OM components including LOS acting synergistically with alpha-MSH. Meningococci were resistant to the anti-microbial activity of alpha-MSH at all concentrations tested.
  
  
  CONCLUSIONS
  Our study demonstrates that a potentially therapeutic neuropeptide exerts pro-inflammatory effects during meningococcal infection in vitro and its use in the treatment of meningitis is contra-indicated.
authors.affiliation: Division of Infection, Inflammation and Immunity, Department of Dermatopharmacology, University of Southampton Medical School, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Jeannette N
authors.initials: JN
authors.lastname: Williams
authors.forename: Kesta L
authors.initials: KL
authors.lastname: Durkin
authors.forename: John E
authors.initials: JE
authors.lastname: Heckels
authors.forename: Peter S
authors.initials: PS
authors.lastname: Friedmann
authors.forename: Eugene
authors.initials: E
authors.lastname: Healy
authors.forename: Myron
authors.initials: M
authors.lastname: Christodoulides
mesh_terms: D001422:Bacterial Adhesion / Q000187:drug effects; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008578:Meninges / Q000187:drug effects / Q000382:microbiology* / Q000503:physiopathology*; D008585:Meningitis, Meningococcal / Q000378:metabolism / Q000503:physiopathology*; D009345:Neisseria meningitidis / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D000521:alpha-MSH / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D000521:alpha-MSH; D000242:Cyclic AMP
references.citation: J Leukoc Biol. 2000 Feb;67(2):233-9
references.pmid: 10670585
references.citation: Peptides. 1996;17(4):675-9
references.pmid: 8804079
references.citation: J Biol Chem. 1996 May 3;271(18):10654-9
references.pmid: 8631871
references.citation: Infect Dis Clin North Am. 1999 Sep;13(3):527-48, v-vi
references.pmid: 10470554
references.citation: Am J Pathol. 2006 Jun;168(6):1921-30
references.pmid: 16723707
references.citation: Nat Immunol. 2005 Jun;6(6):558-64
references.pmid: 15908937
references.citation: Lancet. 1991 Mar 2;337(8740):514-7
references.pmid: 1705642
references.citation: Crit Care Med. 2000 May;28(5):1403-7
references.pmid: 10834686
references.citation: Neuroimmunomodulation. 1996 Sep-Oct;3(5):259-84
references.pmid: 9218248
references.citation: Neuroimmunomodulation. 1997 Jan-Feb;4(1):37-41
references.pmid: 9326743
references.citation: Antimicrob Agents Chemother. 1998 Oct;42(10):2745-6
references.pmid: 9756788
references.citation: J Neuroimmunol. 2001 May 1;116(1):56-61
references.pmid: 11311330
references.citation: Neurotox Res. 2005 Nov;8(3-4):267-76
references.pmid: 16371321
references.citation: Am J Physiol. 1999 May;276(5):R1289-94
references.pmid: 10233018
references.citation: FEBS Lett. 1996 Feb 19;380(3):237-40
references.pmid: 8601432
references.citation: Clin Microbiol Rev. 2000 Jan;13(1):144-66, table of contents
references.pmid: 10627495
references.citation: Bioconjug Chem. 2007 May-Jun;18(3):765-72
references.pmid: 17348700
references.citation: Microb Pathog. 2003 Mar;34(3):121-30
references.pmid: 12631473
references.citation: J Immunol. 1998 Sep 15;161(6):2873-80
references.pmid: 9743348
references.citation: Annu Rev Genet. 2003;37:67-90
references.pmid: 14616056
references.citation: Acta Paediatr. 2000 Jul;89(7):803-5
references.pmid: 10943961
references.citation: Ann N Y Acad Sci. 1999 Oct 20;885:1-21
references.pmid: 10816638
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8686-90
references.pmid: 9238038
references.citation: Inflammation. 1999 Dec;23(6):557-67
references.pmid: 10565569
references.citation: J Biol Chem. 1998 Nov 6;273(45):29847-56
references.pmid: 9792701
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8016-20
references.pmid: 7544012
references.citation: Infect Immun. 2002 Aug;70(8):4035-44
references.pmid: 12117909
references.citation: J Exp Med. 2006 Mar 20;203(3):563-71
references.pmid: 16492802
references.citation: Exp Neurol. 1999 Jun;157(2):359-65
references.pmid: 10364447
references.citation: J Biol Chem. 2000 May 26;275(21):15629-36
references.pmid: 10821844
references.citation: ScientificWorldJournal. 2006 Oct 02;6:1241-6
references.pmid: 17028769
references.citation: Mol Microbiol. 2000 May;36(4):817-29
references.pmid: 10844670
references.citation: Oncogene. 2002 Nov 14;21(52):8037-46
references.pmid: 12439754
references.citation: Infect Immun. 2006 Dec;74(12):6982-91
references.pmid: 17030578
references.citation: J Infect Dis. 1982 Oct;146(4):568
references.pmid: 6126510
references.citation: Am J Physiol Endocrinol Metab. 2003 Mar;284(3):E468-74
references.pmid: 12556347
references.citation: Peptides. 1998;19(6):1099-104
references.pmid: 9700761
references.citation: J Immunol. 1996 Apr 1;156(7):2517-21
references.pmid: 8786313
references.citation: Annu Rev Nutr. 2004;24:133-49
references.pmid: 15189116
references.citation: Mol Cell Endocrinol. 1997 Apr 4;128(1-2):171-7
references.pmid: 9140088
references.citation: Life Sci. 2002 Jul 5;71(7):747-50
references.pmid: 12074933
references.citation: Curr Protein Pept Sci. 2002 Dec;3(6):623-8
references.pmid: 12470216
references.citation: Immunol Today. 1997 Mar;18(3):140-5
references.pmid: 9078687
references.citation: Exp Dermatol. 2004 Dec;13(12):748-54
references.pmid: 15560758
references.citation: J Neuroimmunol. 2007 Mar;184(1-2):45-52
references.pmid: 17210186