The Journal of Experimental Medicine
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Published online 14 July 2003 doi:10.1084/jem.20030159
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© Rockefeller University Press, 0022-1007/2003/7/191 $5.00
The Journal of Experimental Medicine, Volume 198, Number 2, 191-199

Interleukin 1{alpha} Promotes Th1 Differentiation and Inhibits Disease Progression in Leishmania major–susceptible BALB/c Mice

Esther von Stebut1, Jan M. Ehrchen2, Yasmine Belkaid3, Susanna Lopez Kostka1, Katharina Mölle1, Jürgen Knop1, Cord Sunderkötter2 and Mark C. Udey4

1 Department of Dermatology, University of Mainz, Mainz 55131, Germany
2 Institute of Experimental Dermatology, University of Münster, Münster 48149, Germany
3 Department of Molecular Immunology, Children's Hospital Research Foundation, University of Cincinnati, OH 45229
4 Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Dr. Esther von Stebut, Department of Dermatology, University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Phone: 49-6131-175731; Fax: 49-6131-176614; E-mail: vonstebu{at}mail.uni-mainz.de

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-1{alpha} in response to lipopolysaccharide/interferon {gamma} or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1{alpha} mRNA accumulation in lymph nodes of L. major–infected BALB/c mice was ~3-fold lower than that in C57BL/6 mice. Local injections of IL-1{alpha} during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major–infected BALB/c mice, IL-1{alpha} administration resulted in increased Th1- and strikingly decreased Th2-cytokine production. IL-1{alpha} and IL-12 treatments were similarly effective, and IL-1{alpha} efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1{alpha} 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.

Key Words: dendritic cell • IL-1 • Leishmania major • infection • T helper cell type 1/T helper cell type 2 immune response


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