Analyses of the immunoregulatory mechanisms by IL-12-related cytokines and their receptors

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Cytokine/cytokine receptor network is critical in the establishment of immune reaction against various pathogens. We have generated a line of mice deficient for IL-27 receptor (WSX-1) gene and have proved that the mice show remarkable susceptibility against Leishmania major infection by impaired IFN-gamma production. By additional elucidation of the signal transduction mechanisms downstream of IL-27R, we have shown that IL-27/IL-27R (WSX-1) is critical in the initial commitment of Th1 differentiation, prior to IL-12. In addition, IL-27/WSX-1 is also shown to have immunoregulatory function by suppression of pro-inflammatory cytokine production during some protozoan infection. In the current study, we further analyzed the immunoregulatory roles of IL-27 and reported that, due to the augmented inflammatory responses in the absence of IL-27 signaling, allergic asthma exacerbated and also that lethal systemic inflammation occurred during Mycobacterium tuberculosis infection. In MRL/lpr mice, which develop human systemic lupus erythematosus-like autoimmune disease, lack of IL-27R was accompanied with membranous glomerulonephritis (MGN), instead of diffuse proliferative glomerulonephritis in the wild-type mice. To the best of our knowledge, this is the first presentation of a line of model mice that spontaneously develop MGN. For the dual roles of IL-27, we also examined the signal transduction mechanisms and have found that, for Th1 induction, STAT1 activation is critical and that, for immunoregulation, STAT3 activation is important ; further elucidation of the roles and mechanisms of IL-27 is required for therapeutic application of IL-27.