TGFbeta directs gene expression of activated microglia to an anti-inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes.
In experimental autoimmune encephalomyelitis, the acute phase of the disease is produced by T-helper lymphocyte type 1 (TH1), which produces mainly TNFalpha and IFNgamma. Recovery from the disease is mediated by T-helper lymphocyte types 2 and 3 (TH2/TH3), which, among other cytokines, produce transforming growth factor beta (TGFbeta). To address the influence of TGFbeta on TH1-induced gene expression, microarray technology was used on murine primary microglial cells stimulated with IFNgamma and TNFalpha in the absence or presence of TGFbeta. The resulting data from an investigation of up to 5,500 genes provided the notion that TGFbeta prevents the induction of a proinflammatory gene program within microglia exposed to a TH1 milieu. TH1 cytokines upregulated 175 genes comprising cytokine, chemokine, and genes involved in host response to infection and the TNFalpha/IFNgamma intracellular signaling pathway. It is observed that TGFbeta inhibits expression of 25% of the TNFalpha/IFNgamma-induced genes and a further 66 TNFalpha/IFNgamma-independent genes. The focus of TGFbeta inhibition is observed to be directed in genes involved in chemotaxis (IL-15, CXCL1, CXCL2, CCL3, CCL4, CCL5, CCL9), chemokine receptors (CCR5, CCR9), LIF receptor, and FPR2, and on genes mediating cell migration (MMP9, MMP13, MacMARCKS, endothelin receptor B, Ena/VASP, Gas7), apoptosis (FAS, TNF, TNF receptor, caspase-1 and -11), and host response to infection (toll-like receptor 6, Mx-1, and MARCO). Taken collectively, the data strongly suggest that one of the main effects of TGFbeta is to impair cell entry into the CNS and to hinder migration of microglia in the CNS parenchyma.
Paglinawan
Rey
R
Section of Clinical Immunology, Department of Internal Medicine, University Hospital Zürich, Zürich, Switzerland.
Malipiero
Ursula
U
Schlapbach
Ralph
R
Frei
Karl
K
Reith
Walter
W
Fontana
Adriano
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D018925:Chemokines / Q000235:genetics*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000276:immunology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053781:Transforming Growth Factor beta2
D018925:Chemokines; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2