Prostaglandin E2 is a major inhibitor of dendritic cell maturation and function in Ixodes scapularis saliva.
Tick saliva is thought to contain a number of molecules that prevent host immune and inflammatory responses. In this study, the effects of Ixodes scapularis saliva on cytokine production by bone marrow-derived dendritic cells (DCs) from C57BL/6 mice stimulated by TLR-2, TLR-4, and TLR-9 ligands were studied. Saliva at remarkably diluted concentrations (<1/2000) promotes a dose-dependent inhibition of IL-12 and TNF-alpha production induced by all TLR ligands used. Using a combination of fractionation techniques (microcon filtration, molecular sieving, and reversed-phase chromatography), we unambiguously identified PGE(2) as the salivary inhibitor of IL-12 and TNF-alpha production by DCs. Moreover, we have found that I. scapularis saliva (dilution 1/200; approximately 10 nM PGE(2)) marginally inhibited LPS-induced CD40, but not CD80, CD86, or MHC class II expression. In addition, saliva significantly suppressed the ability of DCs to stimulate Ag-specific CD4(+) T cell proliferation and IL-2 production. Notably, the effect of saliva on DC maturation and function was reproduced by comparable concentrations of standard PGE(2). These findings indicate that PGE(2) accounts for most inhibition of DC function observed with saliva in vitro. The role of salivary PGE(2) in vector-host interaction and host immune modulation and inflammation in vivo is also discussed. This study is the first to identify molecularly a DC inhibitor from blood-sucking arthropods.
Sá-Nunes
Anderson
A
Section of Vector Biology, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases/National Institutes of Health, Rockville, MD 20852, USA.
Bafica
André
A
Lucas
David A
DA
Conrads
Thomas P
TP
Veenstra
Timothy D
TD
Andersen
John F
JF
Mather
Thomas N
TN
Ribeiro
José M C
JM
Francischetti
Ivo M B
IM
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000737:chemistry / Q000502:physiology*; D005260:Female; D006131:Growth Inhibitors / Q000737:chemistry / Q000502:physiology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D018884:Ixodes / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012463:Saliva / Q000737:chemistry / Q000276:immunology*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D051193:Toll-Like Receptors; D015232:Dinoprostone