IL-4-Independent Inhibition of IL-12 Responsiveness DuringLeishmania amazonensisInfection

Abstract

Leishmania amazonensis induces a nonhealing infection in C3H mice, whereas infection with Leishmania major is self-healing. We found that C3H mice infected with L. amazonensis exhibited decreased IL-12 production, which could account for the susceptibility to this organism. However, exogenous IL-12 administration failed to induce a healing immune response. The failure of L. amazonensis-infected C3H mice to respond to IL-12 was associated with a specific defect in IL-12 receptor β2 (IL-12Rβ2) mRNA expression by CD4+ T cells. Furthermore, decreased IL-12Rβ2 mRNA expression correlated with a decrease in the IL-12-signaling capacity of the lymph node (LN) cells. IL-4 did not contribute to susceptibility or down-regulation of the IL-12Rβ2 subunit, because IL-4−/− mice remained susceptible to L. amazonensis infection, even after IL-12 administration, and CD4+ cells from infected IL-4−/− mice also had reduced expression of IL-12Rβ2 mRNA. These results demonstrate that regulation of the IL-12 receptor, independent of IL-4, is a point of control for the immune response to leishmaniasis. In contrast to experimental L. major infections, where host genetics control susceptibility, these studies demonstrate that the lack of IL-12 responsiveness may be dictated by the pathogen, rather than the host.

Down-regulation of dendritic cell signaling pathways by Leishmania amazonensis amastigotes

“…Resolution of L. major in genetically resistant mice is ascribed to a polarized Th1 immune response, while the susceptibility in BALB/c mice is attributable to selective expansion of Th2 cells (Sacks and Noben-Trauth, 2002). However, we and others have found that La infection results in nonhealing disease in most inbred mouse strains due to the induction of a weak, Th1/Th2 mixed response (Ji et al, 2002;Jones et al, 2000). The deficient Th1 response seen in La-infected mice is due largely to profound, multiple impairments in numerous cytokines, chemokines, and their corresponding receptors at an early stage of the infection (Ji et al, 2003).…”

An Effect of Parasite-Encoded Arginase on the Outcome of Murine Cutaneous Leishmaniasis

“…Whereas a majority of inbred mouse strains develop self-healing lesions when infected s.c. with L. major, virtually all mice develop rapidly growing large nonhealing lesions full of parasites following s.c. L. mexicana infection (40,41). BALB/c mice are an exception in that both parasites cause progressive disease (3,4,40,41).…”

“…1 and 3) However, the contribution of type 2 cytokines to progressive infection with other Leishmania species is variable. For instance, during L. chagasi infection the type 1 response is inhibited by TGF-␤ (42), whereas type 1 immunity is inhibited by other non-IL-4 factors during infection with L. mexicana and Leishmania donovani (4,43).…”

“…In contrast, the immunological response of mice susceptible to infection by different species of Leishmania is highly variable. Susceptibility to Leishmania major is mediated through expansion of a strong type 2 immune response against a predominant Ag (Leishmania homologue of receptors for activated C-kinase) leading to IL-4 and IL-13 expression, whereas suppression of a type 1 response without Th2 expansion is characteristic of other species (3,4). TGF-␤ is a major factor suppressing the type 1 immune response during infection with Leishmania chagasi (5).…”

“…Interestingly, the amino acid arginine appears to play a key role in the mechanism by which Leishmania survive intracellularly in the mammalian host (7). Macrophages harbor two competing pathways for arginine metabolism initiated by the enzymes inducible NO synthase (iNOS) 4 and arginase, respectively (8,9). The first pathway involves IFN-␥ activation of NOS2 and produces its protein product iNOS.…”