Seshadri Sudarshan, Duncan Michelle D, Hart Judith M, Gavrilin Mikhail A, Wewers Mark D
Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, USA.
J Immunol. 2007 Jul 15;179(2):1274-81. doi: 10.4049/jimmunol.179.2.1274.
Macrophages and their precursors, monocytes, are key cells involved in the innate immune response. Although both monocytes and macrophages produce caspase-1, the key enzyme responsible for pro-IL-1beta processing; macrophages are limited in their ability to activate the enzyme and release functional IL-1beta. In this context, because mutations in the pyrin gene (MEFV) cause the inflammatory disorder familial Mediterranean fever, pyrin is believed to regulate IL-1beta processing. To determine whether variations in pyrin expression explain the difference between monocytes and macrophages in IL-1beta processing and release, pyrin was studied in human monocytes and monocyte-derived macrophages. Although monocytes express pyrin mRNA and protein, which is readily inducible by endotoxin, monocyte-derived macrophages express significantly less pyrin mRNA and protein. Pyrin levels directly correlated with IL-1beta processing in monocytes and macrophages; therefore, we asked whether pyrin might promote IL-1beta processing and release. HEK293 cells were transfected with pyrin, caspase-1, apoptotic speck protein with a caspase recruitment domain, and IL-1beta. Pyrin induced IL-1beta processing and release in a dose-dependent manner. Conversely, pyrin small interference RNA suppressed pro-IL-1beta processing in both THP-1 cells and fresh human monocytes. In summary, both pyrin expression and IL-1beta processing and release are diminished upon the maturation of monocytes to macrophages. When pyrin is ectopically expressed or silenced, IL-1beta processing and release parallels the level of pyrin. In conclusion, in the context of endotoxin-induced activation of mononuclear phagocytes, pyrin augments IL-1beta processing and release.
巨噬细胞及其前体细胞单核细胞是参与固有免疫反应的关键细胞。尽管单核细胞和巨噬细胞都能产生半胱天冬酶 -1，即负责前白细胞介素 -1β加工的关键酶；但巨噬细胞激活该酶并释放功能性白细胞介素 -1β的能力有限。在这种情况下，由于吡啉基因（MEFV）的突变会导致炎性疾病家族性地中海热，因此人们认为吡啉可调节白细胞介素 -1β的加工过程。为了确定吡啉表达的差异是否能解释单核细胞和巨噬细胞在白细胞介素 -1β加工和释放方面的差异，研究人员对人单核细胞和单核细胞衍生的巨噬细胞中的吡啉进行了研究。尽管单核细胞表达吡啉mRNA和蛋白质，且内毒素可轻易诱导其表达，但单核细胞衍生的巨噬细胞表达的吡啉mRNA和蛋白质明显较少。吡啉水平与单核细胞和巨噬细胞中的白细胞介素 -1β加工直接相关；因此，我们探讨了吡啉是否可能促进白细胞介素 -1β的加工和释放。将吡啉、半胱天冬酶 -1、具有半胱天冬酶募集结构域的凋亡斑点蛋白和白细胞介素 -1β转染到人胚肾293细胞中。吡啉以剂量依赖的方式诱导白细胞介素 -1β的加工和释放。相反，吡啉小干扰RNA抑制了THP -1细胞和新鲜人单核细胞中前白细胞介素 -1β的加工。总之，单核细胞成熟为巨噬细胞后，吡啉表达以及白细胞介素 -1β的加工和释放均减少。当吡啉异位表达或沉默时，白细胞介素 -1β的加工和释放与吡啉水平平行。总之，在内毒素诱导的单核吞噬细胞激活过程中，吡啉增强了白细胞介素 -1β的加工和释放。
