Contribution of Langerhans cell-derived IL-18 to contact hypersensitivity.
The epidermal Langerhans cells (LC), a member of the dendritic cell family, and the LC-derived cytokine IL-12 play a pivotal role in the initiation of contact hypersensitivity (CHS), a Th1 immune response in the skin. Because IL-18, another LC-derived cytokine, shares functional and biological properties with IL-12, we examined a potential role for IL-18 in CHS initiation. Our studies demonstrated that during the induction phase of murine CHS, IL-18 mRNA was significantly up-regulated in the skin-draining lymph nodes (LN). Migratory hapten-modified LC in LN expressed high levels of IL-18 mRNA and secreted functional IL-18 protein. LN cells produced significant amounts of IFN-gamma following in vitro IL-12 stimulation, which could be partially blocked by anti-IL-18 Ab, suggesting a synergistic role for endogenous IL-18 in IFN-gamma production by LN cells. Because mature IL-18 requires cleavage of immature precursors by caspase-1, we further examined IL-12-induced IFN-gamma production in caspase-1(-/-) LN cells. An impaired IFN-gamma production was seen in caspase-1(-/-) LN cells, which could be restored by addition of exogenous IL-18, supporting a role for caspase-1-cleaved, mature IL-18 in IFN-gamma production. Finally, in vivo studies showed that CHS responses were significantly inhibited in mice treated with neutralizing IL-18 Ab as well as in caspase-1(-/-) mice deficient in mature IL-18, indicating functional relevance for IL-18 in CHS. Taken together, our studies demonstrate that LC-derived IL-18 significantly contributes to CHS initiation.
Wang
Binghe
B
Department of Dermatology, Johns Hopkins University, Baltimore, MD 21287, USA.
Feliciani
Claudio
C
Howell
Brandon G
BG
Freed
Irwin
I
Cai
Qinchao
Q
Watanabe
Hideaki
H
Sauder
Daniel N
DN
D000279:Administration, Cutaneous; D000818:Animals; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D003877:Dermatitis, Contact / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D007114:Immunization; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007801:Langerhans Cells / Q000276:immunology* / Q000378:metabolism*; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010081:Oxazolone / Q000008:administration & dosage / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D006241:Haptens; D007106:Immune Sera; D020382:Interleukin-18; D012333:RNA, Messenger; D010081:Oxazolone; D018664:Interleukin-12; D007371:Interferon-gamma; D020170:Caspase 1