title: Prostaglandin E(2) in tick saliva regulates macrophage cell migration and cytokine profile.
abstract: BACKGROUND
  Ticks are obligate hematophagous ectoparasites that suppress the host's immune and inflammatory responses by secreting immuno-modulatory and anti-inflammatory molecules in their saliva. In previous studies we have shown that tick salivary gland extract (SGE) and saliva from Dermacentor variabilis have distinct effects on platelet-derived growth factor (PDGF)-stimulated IC-21 macrophage and NIH3T3-L1 fibroblast migration. Since tick saliva contains a high concentration of prostaglandin E2 (PGE2), a potent modulator of inflammation, we used a PGE2 receptor antagonist to evaluate the role of PGE2 in the different migratory responses induced by saliva and its impact on macrophage cytokine profile.
  
  
  METHODS
  Adult ticks were fed on female New Zealand white rabbits for 5-8 days. Female ticks were stimulated with dopamine/theophylline to induce salivation and saliva was pooled. Competitive enzyme immunoassays (EIA) were used to measure saliva PGE2 content and the changes in macrophage intracellular cyclic adenosine monophosphate (cAMP) levels. The effects of tick saliva on macrophage and fibroblast migration were assessed in the absence and presence of the PGE2 receptor antagonist, AH 6809, using blind well chamber assays. A cytokine antibody array was used to examine the effects of tick saliva on macrophage cytokine secretion. Statistical significance was determined by one-way ANOVA; Student Newman-Kuels post-test was used for multiple comparisons.
  
  
  RESULTS
  The saliva-induced increase in PDGF-stimulated macrophage migration was reversed by AH 6809. The inhibition of PDGF-stimulated fibroblast migration by saliva was also antagonist-sensitive. Tick saliva induced macrophages to secrete copious amounts of PGE2, and conditioned medium from these cells caused an AH 6809-sensitive inhibition of stimulated fibroblast migration, showing that macrophages can regulate fibroblast activity. We show that tick saliva decreased the secretion of the pro-inflammatory cytokines regulated and normal T cell expressed and secreted (RANTES/CCL5), tumor necrosis factor-alpha (TNF-α), and soluble TNF receptor I (sTNFRI) through a PGE2-dependent mechanism mediated by cAMP. Saliva had similar effects on lipopolysaccharide (LPS) stimulated macrophages.
  
  
  CONCLUSIONS
  Our data show that ticks utilize salivary PGE2 to subvert the ability of macrophages to secrete pro-inflammatory mediators and recruit fibroblasts to the feeding lesion, therefore inhibiting wound healing.
authors.affiliation: Department of Biological Sciences, The University of Memphis, 239 Ellington Hall, 3700 Walker Avenue, Memphis TN, 38152, USA. nmpoole@memphis.edu.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Poole
authors.forename: Gayatri
authors.initials: G
authors.lastname: Mamidanna
authors.forename: Richard A
authors.initials: RA
authors.lastname: Smith
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Coons
authors.forename: Judith A
authors.initials: JA
authors.lastname: Cole
mesh_terms: D000818:Animals; D060829:Arthropod Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism*; D003870:Dermacentor / Q000737:chemistry / Q000276:immunology; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009520:New Zealand; D011817:Rabbits; D012463:Saliva / Q000737:chemistry* / Q000276:immunology
chemical_list: D060829:Arthropod Proteins; D016207:Cytokines; D015232:Dinoprostone
references.citation: J Exp Med. 1971 Aug 1;134(2):335-50
references.pmid: 4326994
references.citation: Clin Exp Immunol. 2001 Feb;123(2):323-30
references.pmid: 11207665
references.citation: J Exp Med. 1996 Sep 1;184(3):883-91
references.pmid: 9064348
references.citation: PLoS One. 2009 Dec 30;4(12):e8514
references.pmid: 20041127
references.citation: J Immunol. 1976 Apr;116(4):911-4
references.pmid: 1254971
references.citation: Parasite Immunol. 2007 Apr;29(4):169-77
references.pmid: 17371454
references.citation: Exp Parasitol. 2008 Jul;119(3):391-7
references.pmid: 18492598
references.citation: Clin Exp Immunol. 1995 Sep;101(3):502-6
references.pmid: 7664497
references.citation: J Clin Invest. 1998 Jan 15;101(2):311-20
references.pmid: 9435302
references.citation: Infect Immun. 2004 May;72(5):2989-94
references.pmid: 15102811
references.citation: Wound Repair Regen. 2006 Sep-Oct;14(5):633-43
references.pmid: 17014677
references.citation: Annu Rev Med. 1994;45:491-503
references.pmid: 8198398
references.citation: J Biomed Mater Res A. 2011 Dec 15;99(4):630-7
references.pmid: 21954011
references.citation: Trends Immunol. 2001 Feb;22(2):83-7
references.pmid: 11286708
references.citation: J Biol Chem. 1988 Apr 15;263(11):5380-4
references.pmid: 3162731
references.citation: Parasitol Today. 1989 Feb;5(2):47-56
references.pmid: 15463179
references.citation: Exp Parasitol. 1990 May;70(4):382-8
references.pmid: 2157607
references.citation: Annu Rev Entomol. 1987;32:463-78
references.pmid: 2880553
references.citation: J Immunol. 1982 Dec;129(6):2469-73
references.pmid: 6216284
references.citation: J Thromb Haemost. 2009 Nov;7(11):1855-64
references.pmid: 19624457
references.citation: J Biol Chem. 2007 Sep 14;282(37):27250-27258
references.pmid: 17640866
references.citation: Blood. 1996 Aug 1;88(3):922-7
references.pmid: 8704250
references.citation: J Biol Chem. 2011 Jan 21;286(3):2111-20
references.pmid: 21097507
references.citation: Infect Agents Dis. 1995 Sep;4(3):143-52
references.pmid: 8548192
references.citation: Parasitol Today. 1996 Oct;12(10):388-96
references.pmid: 15275289
references.citation: Nat Rev Immunol. 2002 Oct;2(10):787-95
references.pmid: 12360216
references.citation: Exp Parasitol. 2011 Mar;127(3):665-71
references.pmid: 21145320
references.citation: Parasit Vectors. 2011 Sep 28;4:187
references.pmid: 21951834
references.citation: Ticks Tick Borne Dis. 2013 Feb;4(1-2):120-7
references.pmid: 23168047
references.citation: J Biol Chem. 2011 Apr 1;286(13):10960-9
references.pmid: 21270122
references.citation: PLoS One. 2008;3(12):e3987
references.pmid: 19096526
references.citation: Br J Pharmacol. 1979 Mar;65(3):517-24
references.pmid: 371730
references.citation: J Immunol. 2009 Apr 1;182(7):3945-6
references.pmid: 19299688
references.citation: Arch Insect Biochem Physiol. 2009 Aug;71(4):236-53
references.pmid: 19514082
references.citation: J Clin Invest. 2001 Oct;108(8):1229-35
references.pmid: 11602631
references.citation: Thromb Haemost. 2005 Jul;94(1):167-74
references.pmid: 16113800
references.citation: J Immunol. 1993 Aug 1;151(3):1205-13
references.pmid: 8335925
references.citation: Parasite Immunol. 2010 Jun;32(6):460-3
references.pmid: 20500677
references.citation: Blood. 1997 Oct 1;90(7):2772-83
references.pmid: 9326245
references.citation: Nat Rev Immunol. 2008 Dec;8(12):958-69
references.pmid: 19029990
references.citation: J Immunol. 1989 Dec 1;143(11):3517-23
references.pmid: 2584704
references.citation: J Exp Med. 2008 Sep 1;205(9):2019-31
references.pmid: 18678732
references.citation: Exp Cell Res. 2003 Oct 1;289(2):265-74
references.pmid: 14499627
references.citation: Nature. 1996 Oct 31;383(6603):787-93
references.pmid: 8893001
references.citation: Exp Appl Acarol. 1999 Nov;23(11):915-28
references.pmid: 10668866
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Nov;281(5):L1257-63
references.pmid: 11597918
references.citation: Nat Immunol. 2005 Dec;6(12):1191-7
references.pmid: 16369558
references.citation: Toxicon. 2006 Jan;47(1):1-20
references.pmid: 16364387
references.citation: Clin Exp Immunol. 1995 Sep;101(3):387-9
references.pmid: 7664483
references.citation: J Thromb Haemost. 2009 Nov;7(11):1852-4
references.pmid: 19694942
references.citation: Parasitology. 2005 Mar;130(Pt 3):333-42
references.pmid: 15796016
references.citation: Int J Parasitol. 2011 Feb;41(2):213-23
references.pmid: 20934428
references.citation: Infect Immun. 2009 Jun;77(6):2320-9
references.pmid: 19332533
references.citation: Annu Rev Immunol. 2001;19:163-96
references.pmid: 11244034
references.citation: Exp Parasitol. 1992 Feb;74(1):112-6
references.pmid: 1730268
references.citation: Parasite Immunol. 1998 Apr;20(4):169-74
references.pmid: 9618727
references.citation: J Immunol. 2007 Aug 1;179(3):1497-505
references.pmid: 17641015
references.citation: Exp Cell Res. 1980 Sep;129(1):15-21
references.pmid: 7428810
references.citation: Wound Repair Regen. 2007 Jan-Feb;15(1):122-33
references.pmid: 17244328
references.citation: J Exp Clin Cancer Res. 2011 Mar 05;30:26
references.pmid: 21375766
references.citation: Toxicon. 2010 Dec 15;56(7):1130-44
references.pmid: 20035779
references.citation: J Immunol. 1991 Jan 1;146(1):108-13
references.pmid: 1845802
references.citation: J Leukoc Biol. 2004 Jul;76(1):227-36
references.pmid: 15075356
references.citation: J Parasitol. 1979 Aug;65(4):531-42
references.pmid: 229203
references.citation: Age (Dordr). 2008 Mar;30(1):11-9
references.pmid: 19424869
references.citation: Annu Rev Entomol. 1995;40:245-67
references.pmid: 7810988
references.citation: J Exp Med. 1994 Sep 1;180(3):1077-85
references.pmid: 8064226
references.citation: Immunology. 2005 Feb;114(2):235-45
references.pmid: 15667568
references.citation: J Pharmacol Exp Ther. 2008 Aug;326(2):493-501
references.pmid: 18492946
references.citation: Toxicon. 2010 Dec 15;56(7):1120-9
references.pmid: 19925819
references.citation: Parasit Vectors. 2010 Nov 05;3:103
references.pmid: 21054882
references.citation: J Exp Med. 1985 Feb 1;161(2):332-44
references.pmid: 2982989
references.citation: Parasit Vectors. 2012 Feb 14;5:38
references.pmid: 22333193
references.citation: Physiol Rev. 2003 Jul;83(3):835-70
references.pmid: 12843410
references.citation: Vet Parasitol. 1994 Jun;53(3-4):293-9
references.pmid: 7975125
references.citation: Immunology. 1994 May;82(1):113-6
references.pmid: 8045588
references.citation: Parasit Vectors. 2012 Oct 10;5:229
references.pmid: 23050849
references.citation: J Immunol. 1983 Aug;131(2):768-72
references.pmid: 6306107