Pertussis toxin enhances Th1 responses by stimulation of dendritic cells.
Pertussis toxin (PTX) has been widely used as an adjuvant to induce Th1-mediated organ-specific autoimmune diseases in animal models. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that dendritic cells (DC) stimulated with PTX (PTX-DC) were able to substitute for PTX to promote experimental autoimmune uveitis (EAU). EAU induced by PTX-DC revealed a typical Th1 response, characterized by high uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP)-specific IFN-gamma and IL-12 production in the draining lymph nodes, as well as increased levels of anti-IRBP IgG2a and decreased levels of anti-IRBP IgG1 in the serum of IRBP-immunized mice. Furthermore, PTX-DC preferentially induced T cells to produce the Th1 cytokine, IFN-gamma. After being stimulated with PTX, DC exhibited up-regulation of MHC class II, CD80, CD86, CD40, and DEC205. PTX-DC had also increased allostimulatory capacity and IL-12 and TNF-alpha production. Serum IL-12 was increased in naive mice that received PTX-DC i.p. In addition, PTX activated extracellular signal-regulated kinase in DC. Following the inhibition of extracellular signal-regulated kinase signaling, the maturation of PTX-DC was reduced. Subsequently, the ability of PTX-DC to promote IFN-gamma production by T cells in vitro and to induce EAU in vivo was blocked. The results suggest that PTX might exert an adjuvant effect on DC to promote their maturation and the production of proinflammatory cytokines, thereby eliciting a Th1 response.
Hou
Wanqiu
W
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Wu
Yadi
Y
Sun
Shuhui
S
Shi
Mude
M
Sun
Yue
Y
Yang
Cuihong
C
Pei
Gang
G
Gu
Yundi
Y
Zhong
Cuiping
C
Sun
Bing
B
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000637:transplantation; D005136:Eye Proteins / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000097:blood / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D037342:Pertussis Toxin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D012177:Retinol-Binding Proteins / Q000008:administration & dosage / Q000276:immunology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D014605:Uveitis / Q000201:enzymology / Q000209:etiology / Q000276:immunology / Q000473:pathology; D000099214:Retinol-Binding Proteins, Interstitial
D000276:Adjuvants, Immunologic; D005136:Eye Proteins; D007371:Interferon-gamma; D018664:Interleukin-12; D037342:Pertussis Toxin; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial