TGF-beta1 disrupts endotoxin signaling in microglial cells through Smad3 and MAPK pathways.

Abstract

Human formyl peptide receptor-like 1 and its mouse homologue formyl peptide receptor 2 (FPR2) are G protein-coupled receptors used by a number of exogenous and host-derived chemotactic peptides, including the 42 aa form of beta amyloid peptide, a causative factor of Alzheimer's disease. Functional FPR2 was induced by bacterial LPS in murine microglial cells, the resident phagocytic cells that play a pivotal role in inflammatory and immunological diseases in the CNS. To identify agents that may suppress microglial cell activation under proinflammatory conditions, we investigated the effect of TGF-beta1 on the expression of functional FPR2 by microglial cells activated by LPS. TGF-beta1 dose-dependently inhibited the mRNA expression and function of FPR2 in LPS-activated microglial cells. The inhibitory effect of TGF-beta1 was mediated by Smad3, a key signaling molecule coupled to the TGF-beta receptor, and the transcription coactivator, p300. Also, TGF-beta1 activates MAPKs in microglial cells that became refractory to further stimulation by LPS. These effects of TGF-beta1 culminate in the inhibition of LPS-induced activation of NF-kappaB and the up-regulation of FPR2 in microglial cells. Thus, TGF-beta1 may exert a protective role in CNS diseases characterized by microglial cell activation by proinflammatory stimulants.

• Authors: Yingying Le, Pablo Iribarren, Wanghua Gong, Youhong Cui, Xia Zhang, Ji Ming Wang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 173 Issue 2 Pg. 962-8 (Jul 15 2004) ISSN: 0022-1767 [Print] United States
• PMID: 15240683 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• Lipopolysaccharides
• NF-kappa B
• Nuclear Proteins
• Receptors, Formyl Peptide
• Smad3 Protein
• Smad3 protein, mouse
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Trans-Activators
• Transforming Growth Factor beta
• Transforming Growth Factor beta1
• formyl peptide receptor 2, mouse
• E1A-Associated p300 Protein
• Ep300 protein, mouse
• Mitogen-Activated Protein Kinases

Topics

• Animals
• DNA-Binding Proteins (metabolism)
• E1A-Associated p300 Protein
• Lipopolysaccharides (metabolism)
• Mice
• Microglia (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Nuclear Proteins (metabolism)
• Receptors, Formyl Peptide (metabolism)
• Smad3 Protein
• Trans-Activators (metabolism)
• Transforming Growth Factor beta (metabolism)
• Transforming Growth Factor beta1