Distinct roles for IL-1 receptor type I signaling in early versus established Leishmania major infections

J Invest Dermatol. 2006 Jul;126(7):1582-9. doi: 10.1038/sj.jid.5700309. Epub 2006 Apr 27.


IL-1alpha/beta released by infected dendritic cells (DC) plays a critical role in the development of protective immunity against Leishmania major. Previous studies demonstrated that treatment of susceptible BALB/c mice with IL-1alpha during T-cell priming (days 1-3 post-infection) induced T helper (Th)1-mediated protection. In contrast, we now demonstrate that prolonged treatment with IL-1alpha (for 3 weeks) worsened disease outcome. To characterize the receptor involved, L. major infections in IL-1 receptor type I (IL-1RI) knockout mice were studied. In C57BL/6 IL-1RI-/- mice, the IL-1alpha-mediated protective effect was abrogated. The course of high-dose infection (2 x 10(5) parasites) in IL-1RI-/- mice was not different from controls. Surprisingly, in low-dose infections (10(3) parasites), IL-1RI-/- mice developed approximately 50% smaller lesions compared to wild types, decreased parasite loads and increased IFNgamma/IL-4 ratios. Interestingly, naive Th0 and Th2, but not Th1, cells expressed IL-1RI ex vivo. We conclude that IL-1RI mediates the effect of IL-1alpha in leishmaniasis in C57BL/6 mice. In addition, IL-1 appears to play distinct roles in Th education and maintenance. In early phases of physiologically relevant, low-dose L. major infections, IL-1 facilitates Th1 development from Th0 cells, whereas later on IL-1RI signaling promotes Th2 expansion and worsens disease outcome. Effects of IL-1 on disease outcome may be related to levels of IL-1RI on Th subpopulations.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / analysis
  • Disease Progression
  • Gene Expression Regulation / physiology
  • Interferon-gamma / analysis
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology
  • Interleukin-4 / analysis
  • L-Selectin / analysis
  • Leishmania major / immunology*
  • Leishmaniasis, Cutaneous / immunology
  • Leishmaniasis, Cutaneous / pathology
  • Leishmaniasis, Cutaneous / physiopathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interleukin-1 / genetics*
  • Receptors, Interleukin-1 / physiology*
  • Receptors, Interleukin-1 Type I
  • Signal Transduction / physiology*
  • T-Lymphocytes, Helper-Inducer / chemistry
  • T-Lymphocytes, Helper-Inducer / pathology
  • Th1 Cells / chemistry
  • Th1 Cells / pathology
  • Th1 Cells / physiology
  • Th2 Cells / chemistry
  • Th2 Cells / pathology
  • Th2 Cells / physiology


  • CD4 Antigens
  • Interleukin-1
  • Receptors, Interleukin-1
  • Receptors, Interleukin-1 Type I
  • L-Selectin
  • Interleukin-4
  • Interferon-gamma