Soluble tumor necrosis factor receptor inhibits interleukin 12 production by stimulated human adult microglial cells in vitro.
IL-12 is a cytokine detected in active lesions in multiple sclerosis (MS) and promotes the acquisition of a Th1 cytokine profile by CD4+ T cells. Autoreactive T cells recovered from the central nervous system of animals with experimental autoimmune encephalomyelitis (EAE), a disease model for MS, display this phenotype. We demonstrate that human central nervous system-derived microglia, but not astroglia, can produce IL-12 in vitro. Under basal culture conditions, human adult microglia do not express detectable levels of IL-12, although these cells show some degree of activation as assessed by expression of the immunoregulatory surface molecules HLA-DR and B7 as well as low levels of TNF-alpha mRNA. Following activation with LPS, IL-12 p40 mRNA and p70 protein can be readily detected. IL-12 production is preceded by TNF-alpha production and is inhibited by recombinant soluble human TNF receptor (II)-IgG1 fusion protein (shu-TNF-R). These data indicate regulation of IL-12 by an autocrine-dependent feedback loop, providing an additional mechanism whereby shu-TNF-R, now used in clinical trials in MS, may be exerting its effect.
Becher
B
B
Montréal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Canada.
Dodelet
V
V
Fedorowicz
V
V
Antel
J P
JP
D000328:Adult; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D005333:Fetus / Q000166:cytology; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D017628:Microglia / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12