Novel IL-12 family members shed light on the orchestration of Th1 responses

181

169

Three clonal strain types (I, II, and III) of Toxoplasma gondii predominate worldwide. The outcome of infection in mice is highly dependent on the parasite genotype with type I strains being uniformly virulent, while types II and III are nonvirulent. Interactions with the innate immune response play a major role in determining the outcome of infection in the murine model. To identify key early differences in the innate immune response that contribute to pathogenesis, we examined the cytokine production of macrophages after in vitro infection with parasites of virulent type I and nonvirulent type II genotypes. Infection with type II strain parasites stimulated the production of proinflammatory cytokines, and particularly high levels of the Th1-polarizing cytokine, IL-12. Infection with type II strain parasites stimulated NF-κB nuclear translocation at early time points and led to the up-regulation of mRNA levels of IL-12 and other proinflammatory cytokines that was dependent on the myeloid differentiation factor 88 signaling pathway. Induction of IL-12 required active invasion by live parasites and was not blocked by infection with virulent type I strain parasites, arguing against an active inhibition of signaling. Our findings suggest that early induction of high levels of IL-12 by macrophages infected with type II strain parasites may contribute to more effective control.

Section: Discussionsupporting

confidence: 92%

Production of IL-12 by Macrophages Infected withToxoplasma gondiiDepends on the Parasite Genotype

Robben¹,

Mordue²,

Truscott

et al. 2004

181

169

“…Although it is possible that early, transient, and low-level IL-12 responses might have been missed (as suggested by the flow cytometric analysis in which IL-12-positive cells could be detected after 18 h of incubation with iRBC), it also seems likely that an initial wave of IFN-␥ markedly up-regulates the IL-12 response and that this in turn may further augment the IFN-␥ response, leading to a positive feedback loop from which very high concentrations of proinflammatory cytokines can result. In contrast, previous in vitro studies have reported rapid in vitro induction of IL-12p40 upon stimulation of PBMC with iRBC (4,46), raising the interesting possibility that one of the first cytokines to be induced by iRBC may be IL-23 (a heterodimer composed of p40 and p19) or possibly even IL-27, which contains a p40-related protein (53). Intriguingly, IL-27 has been shown to induce IFN-␥ production by human NK cells independently of, and before IL-12 (54), suggesting that the potential role of this cytokine in the early response to iRBC requires further investigation.…”

Section: Discussionmentioning

confidence: 76%

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Walther

Woodruff

Edele

et al. 2006

141

118

Taking advantage of a sporozoite challenge model established to evaluate the efficacy of new malaria vaccine candidates, we have explored the kinetics of systemic cytokine responses during the prepatent period of Plasmodium falciparum infection in 18 unvaccinated, previously malaria-naive subjects, using a highly sensitive, bead-based multiplex assay, and relate these data to peripheral parasite densities as measured by quantitative real-time PCR. These data are complemented with the analysis of cytokine production measured in vitro from whole blood or PBMC, stimulated with P. falciparum-infected RBC. We found considerable qualitative and quantitative interindividual variability in the innate responses, with subjects falling into three groups according to the strength of their inflammatory response. One group secreted moderate levels of IFN-γ and IL-10, but no detectable IL-12p70. A second group produced detectable levels of circulating IL-12p70 and developed very high levels of IFN-γ and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-β. Proinflammatory responses were associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms, suggesting that the initial innate response may have far-reaching consequences on disease outcome. Furthermore, the in vitro observations on cytokine kinetics presented here, suggest that intact schizont-stage infected RBC can trigger innate responses before rupture of the infected RBC.

“…Similarly, it is also possible that distinct ligands, such as IL-27 (p28 plus EBI-3) vs EBI-3 plus p35 of IL-12 (24,34), bind to the WSX-1 receptor complex in various settings (see Ref. 35 for review). From these points, it is intriguing that mice lacking EBI-3 (a subunit of IL-27) showed defects in NKT cell development (31).…”

Section: Discussionmentioning

confidence: 99%

“…Memory CD4 ϩ T cells resort to IL-23/IL-23R for their proliferation and augmentation of IFN-␥ production (for review, see Refs. [35][36][37]. However, the roles played by members of the expanding IL-12 family are not limited to Th1 differentiation and IFN-␥ production.…”

Section: Discussionmentioning

confidence: 99%

Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

Yamanaka

Hamano

Miyazaki

et al. 2004

Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-γ and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-γ and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.