Transforming growth factor beta1 prevents IL-1beta-induced microglial activation, whereas TNFalpha- and IL-6-stimulated activation are not antagonized.
Microglia rapidly respond to CNS injury, yet the mechanisms leading to their activation and inactivation remain poorly defined. In particular, few studies have established how interactions between inflammatory mediators affect the innate immune response of microglia. To begin to establish how microglia integrate signals from multiple inflammatory mediators, we examined the effects of interleukin 1beta (IL-1beta), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalpha), interferon gamma (IFN-gamma), and transforming growth factor beta1 (TGFbeta1) on both newborn and bulk-isolated adult microglia. To assess the functional state of the cells, we assayed the expression of cyclooxygenase 2 (Cox-2), interleukin 6, and tumor necrosis factor alpha, and two protein tyrosine kinases that have been implicated in microglial responses to activational stimuli, HCK and FAK. These studies demonstrated that IL-1beta, TNFalpha, IL-6, but not IFN-gamma increase the expression of Cox-2, whereas they all increase the expression of HCK and FAK. In these studies, TGFbeta1 either had no effect, or it decreased basal levels of these proteins. TGFbeta1 blocked activation by IL-1beta when given prior to, or simultaneously with, IL-1beta. TGFbeta1 blocked the induction of the tyrosine kinases, Cox-2, and the induction of IL-6 and TNFalpha mRNAs. However, TGFbeta1 was ineffective in antagonizing the induction of Cox-2 by either IL-6 or TNFalpha. We conclude that the TGFbeta receptor signaling cascades intersect with IL-1, but they may not interact with IL-6 or TNFalpha signaling pathways that lead to activation.
Basu
Anirban
A
Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Krady
J Kyle
JK
Enterline
Jonathan R
JR
Levison
Steven W
SW
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001930:Brain Injuries / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D051546:Cyclooxygenase 2; D004347:Drug Interactions / Q000276:immunology; D004660:Encephalitis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D018836:Inflammation Mediators / Q000276:immunology* / Q000494:pharmacology; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D007527:Isoenzymes / Q000187:drug effects / Q000276:immunology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000276:immunology; D051572:Proto-Oncogene Proteins c-hck; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496633:Hck protein, rat; D051572:Proto-Oncogene Proteins c-hck; C496052:Ptk2 protein, rat