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

Abstract

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

TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4+ T cells

“…However, in Leishmania major-infected BALB/c mice, IL-1a enhances Th1 immunity [19]. These observations suggest that IL-1 can act as a nonpolarized enhancer of Th activity.…”

Dendritic Cell-Derived IL-12p40 Homodimer Contributes to Susceptibility in Cutaneous Leishmaniasis in BALB/c Mice

“…In addition, DC-supernatants generally contain ϳ100-to 1,000-fold more IL-12p40 than IL-12p70. Therefore, we chose to apply 2 g of IL-12p80/mouse on days 1, 2, and 3 postinfection-a treatment schedule that has proven to be efficacious for IL-1␣ to protect BALB/c mice from progressive disease (12). For comparison, IL-12p70 was administered in a similar fashion (50 ng/mouse) (12).…”

“…Groups of mice were infected intradermally into ear skin with 2 ϫ 10 5 infectious stage metacyclic promastigotes (12,15). In some experiments, mice were euthanized in wk 3, and DC from draining submandibular LNs were positively selected using anti-CD11c microbeads (Miltenyi Biotec) and plated at 1 ϫ 10 6 cells/200 l in RPMI 1640/5% FCS.…”

“…Lesion sizes were measured weekly using a caliper and ellipsoid volumes were calculated. Organisms present in lesional tissue were enumerated at the indicated times using limiting dilution assays as described previously (12). For determination of cytokine profiles in infected mice, retroauricular LNs were recovered at wk 3 and wk 5 and single-cell suspensions were prepared.…”

“…Purity was determined by assessing the number of CD11c ϩ MHC class II ϩ cells by flow cytometry (10,15). Metacyclic promastigotes or amastigotes of L. major clone VI (MHOM/IL/80/Friedlin) were prepared as described previously (12). Isolated parasites were opsonized with 5% BALB/c normal mouse serum and washed before in vitro or in vivo infections.…”