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TGFβ directs gene expression of activated microglia to an anti‐inflammatory phenotype strongly focusing on chemokine genes and cell migratory genes
Author(s) -
Paglinawan Rey,
Malipiero Ursula,
Schlapbach Ralph,
Frei Karl,
Reith Walter,
Fontana Adriano
Publication year - 2003
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.10286
Subject(s) - biology , ccl3 , cxcl2 , ccl13 , ccl5 , chemokine , immunology , chemokine receptor , cxcl1 , microbiology and biotechnology , inflammation , t cell , ccl2 , immune system , il 2 receptor
In experimental autoimmune encephalomyelitis, the acute phase of the disease is produced by T‐helper lymphocyte type 1 (T H 1), which produces mainly TNFα and IFNγ. Recovery from the disease is mediated by T‐helper lymphocyte types 2 and 3 (T H 2/T H 3), which, among other cytokines, produce transforming growth factor β (TGFβ). To address the influence of TGFβ on T H 1‐induced gene expression, microarray technology was used on murine primary microglial cells stimulated with IFNγ and TNFα in the absence or presence of TGFβ. The resulting data from an investigation of up to 5,500 genes provided the notion that TGFβ prevents the induction of a proinflammatory gene program within microglia exposed to a T H 1 milieu. T H 1 cytokines upregulated 175 genes comprising cytokine, chemokine, and genes involved in host response to infection and the TNFα/IFNγ intracellular signaling pathway. It is observed that TGFβ inhibits expression of 25% of the TNFα/IFNγ‐induced genes and a further 66 TNFα/IFNγ‐independent genes. The focus of TGFβ 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 TGFβ is to impair cell entry into the CNS and to hinder migration of microglia in the CNS parenchyma. © 2003 Wiley‐Liss, Inc.