IL12 is a key candidate for treating malignancies because it is a potent proinflammatory
cytokine, activates T and NK cells, and induces the expression of IFN-γ expression. Although promising in the treatment of malignancies, especially micrometastic lesions, high Gefitinib datasheet toxicity and fatalities were observed in clinical trials mainly due to IFN-γ expression. Therefore, control of excessive induction of IFN-γ may be achieved by using gene therapy instead of an acute dose of recombinant IL12 therapy. Even with gene therapy, a high dose and frequent administrations could trigger liver toxicity; however, IL12-induced toxicity can be prevented or even treated by using IL30, as we discovered in this study. This
observation may be translated to human clinics for safely using IL12 or other proinflammatory cytokine therapy. This conclusion was further supported by the fact that IL30 significantly reduces the ConA-induced liver injury, as reported in this study, and also in agreement with the fact that ConA causes less toxicity in EBI3 knockout mice than in wildtype mice.23, 24 Importantly, multiple lines of evidence from our study suggest that IL30, as an independent cytokine, inhibits IL12-induced liver injury due to the independence of IL27 and EBI3 signaling pathways. This unique discovery reveals that IL30 perhaps is an important therapeutic candidate for preventing not only IL12 and IFN-γ, but other inflammatory cytokine-induced see more liver toxicity. IFN-γ plays a crucial role not only in initiating
innate and adaptive immune responses but also in homeostatic functions that limit inflammation-associated tissue destruction. IFN-γ’s ability to initiate an adaptive immune response is well understood and occurs mainly by way of activation of macrophages and immune cells at the site of inflammation; however, how IFN-γ maintains a crucial role in homeostatic functions is not fully understood. Because IFN-γ administration at the site of the inflammation exacerbates diseases selleck screening library in arthritis and autoimmune diabetes models, yet a lack of IFN-γ seems to enhance the severity of arthritis in the K/BxN model,32 IFN-γ is a key mediator for up-regulation of antiinflammatory cytokines, which are necessary to decrease tissue destruction. So, understanding which particular molecules are signaling downstream of IFN-γ has important therapeutic implications. Our study not only confirms that IFN-γ induces IL30 in vitro but also reveals the biological function of this cytokine. Different from Liu et al.,30 who established that IFN-γ induces IL30 in macrophages in vitro, we found that IL30 is a very potent inhibitor of proinflammatory cytokine-induced hepatotoxicity in vivo.