Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK, OX3 9DS.
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD. 20892.
J Immunol. 2014 Mar 1;192(5):2029-2033. doi: 10.4049/jimmunol.1302549. Epub 2014 Jan 31.
The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1β. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1β in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1β occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1β is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1β production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1-driven tissue pathology in certain disease settings.
内质网（ER）中未正确折叠的蛋白质积累会产生称为 ER 应激的干扰，从而引发未折叠蛋白反应。ER 应激与许多炎症性病理有关，这些病理也与前炎症细胞因子 IL-1β的产生有关。在这项研究中，我们证明了在体外受到 ER 应激的巨噬细胞能够在 LPS 刺激下驱动前体 IL-1β的产生和加工。有趣的是，经典的 NLRP3 炎性小体是可有可无的，因为在缺乏衔接蛋白 ASC 的情况下，前体 IL-1β的成熟正常发生。相比之下，前体 IL-1β的加工完全依赖于半胱天冬酶-8。有趣的是，我们发现， unfolded protein response 转录因子 XBP1 和 CHOP 以及 TLR4 衔接分子 MyD88 都不是 caspase-8 激活所必需的。相反，caspase 的激活和 IL-1β的产生都需要替代的 TLR4 衔接分子 TRIF。这条途径可能有助于某些疾病状态下由 IL-1 驱动的组织病理学。
