Interleukin 1alpha promotes Th1 differentiation and inhibits disease progression in Leishmania major-susceptible BALB/c mice.
Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12-dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1alpha in response to lipopolysaccharide/interferon gamma or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1alpha mRNA accumulation in lymph nodes of L. major-infected BALB/c mice was approximately 3-fold lower than that in C57BL/6 mice. Local injections of IL-1alpha during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major-infected BALB/c mice, IL-1alpha administration resulted in increased Th1- and strikingly decreased Th2-cytokine production. IL-1alpha and IL-12 treatments were similarly effective, and IL-1alpha efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1alpha acts in conjunction with IL-12 to influence Th-development in cutaneous leishmaniasis and prevents disease progression in susceptible BALB/c mice, perhaps by enhancing DC-induced Th1-education. Differential production of IL-1 by C57BL/6 and BALB/c mice may provide a partial explanation for the disparate outcomes of infection in these mouse strains.
Von Stebut
Esther
E
Department of Dermatology, University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. vonstebu@mail.uni-mainz.de
Ehrchen
Jan M
JM
Belkaid
Yasmine
Y
Kostka
Susanna Lopez
SL
Molle
Katharina
K
Knop
Jurgen
J
Sunderkotter
Cord
C
Udey
Mark C
MC
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D007375:Interleukin-1 / Q000627:therapeutic use*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012867:Skin / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
D007375:Interleukin-1