Distinct roles for IL-1 receptor type I signaling in early versus established Leishmania major infections.
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.
Kostka
Susanna Lopez
SL
Department of Dermatology, Johannes Gutenberg-University Mainz, Mainz, Germany.
Knop
Jürgen
J
Konur
Abdo
A
Udey
Mark C
MC
von Stebut
Esther
E
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000502:physiology; D007371:Interferon-gamma / Q000032:analysis; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D015847:Interleukin-4 / Q000032:analysis; D019041:L-Selectin / Q000032:analysis; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D015398:Signal Transduction / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000737:chemistry / Q000473:pathology; D018417:Th1 Cells / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D018418:Th2 Cells / Q000737:chemistry / Q000473:pathology / Q000502:physiology
D015704:CD4 Antigens; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D019041:L-Selectin; D015847:Interleukin-4; D007371:Interferon-gamma