IL-1-induced inflammation promotes development of leishmaniasis in susceptible BALB/c mice.
The role of host-derived IL-1 on the course of Leishmania major infection in susceptible BALB/c mice was assessed. Manifestations of the disease were more severe in mice deficient in the physiological inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra) in comparison with control mice. In mice lacking one of the IL-1 genes (IL-1alpha or IL-1beta), there was delayed development of the disease and more attenuated systemic inflammatory responses. IL-1alpha-deficient mice were slightly more resistant to L. major infection compared with IL-1beta-knockout mice. During disease progression in IL-1Ra KO and control mice, myeloid-derived suppressor cells invaded the spleen, concomitant to suppression of T cell-mediated immunity and expression of systemic high levels of pro-inflammatory cytokines. In IL-1-deficient mice, T(h)1 responses were still apparent, even at late stages of the disease. Thus, dose-dependent effects of IL-1 were shown to influence the pathogenesis of murine leishamaniasis in susceptible BALB/c mice. Physiological and supra-physiological levels of IL-1 in the microenvironment promoted an exacerbated form of disease, whereas sub-physiological doses of IL-1 induced a less progressive disease. Thus, manipulation of IL-1 levels in the host, using the IL-1Ra or specific antibodies, has the potential to alleviate symptoms of visceral manifestations of leishmaniasis.
Voronov
Elena
E
Shraga Segal Department of Microbiology and Immunology, The Cancer Research Center, Faculty of Health Sciences and Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. elena@bgu.ac.il
Dotan
Shahar
S
Gayvoronsky
Lubov
L
White
Rosalyn M
RM
Cohen
Idan
I
Krelin
Yakov
Y
Benchetrit
Fabrice
F
Elkabets
Moshe
M
Huszar
Monika
M
El-On
Joseph
J
Apte
Ron N
RN
D000818:Animals; D004198:Disease Susceptibility; D007249:Inflammation / Q000473:pathology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology*; D053582:Interleukin-1alpha / Q000172:deficiency / Q000235:genetics; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout
D007375:Interleukin-1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta