Toll-like receptor 4 signaling augments transforming growth factor-β responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma.

Because recent studies implicate Toll-like receptors (TLRs) in the pathogenesis of fibrosis, we sought to investigate the in vitro and in vivo role and mechanism of TLR4-mediated fibroblast responses in fibrogenesis. We found that TLR4 was constitutively expressed, and accumulation of endogenous TLR4 ligands significantly elevated, in lesional skin and lung tissues from patients with scleroderma. Activation of TLR4 signaling in explanted fibroblasts resulted in enhanced collagen synthesis and increased expression of multiple genes involved in tissue remodeling and extracellular matrix homeostasis.

The transcriptional cofactor nab2 is induced by tgf-Beta and suppresses fibroblast activation: physiological roles and impaired expression in scleroderma.

By stimulating collagen synthesis and myofibroblasts differentiation, transforming growth factor-beta (TGF- beta) plays a pivotal role in tissue repair and fibrosis. The early growth response-1 (Egr-1) transcription factor mediates profibrotic TGF-beta responses, and its expression is elevated in biopsies from patients with scleroderma. NGF1-A-binding protein 2 (Nab2) is a conserved transcriptional cofactor that directly binds to Egr-1 and positively or negatively modulates Egr-1 target gene transcription.

Essential roles for early growth response transcription factor Egr-1 in tissue fibrosis and wound healing.

The early growth response gene (Egr-1) codes for a zinc finger transcription factor that has important roles in the regulation of cell growth, differentiation, and survival. Aberrant Egr-1 expression is implicated in carcinogenesis, inflammation, atherosclerosis, and ischemic injury. We reported previously that normal fibroblasts stimulated by transforming growth factor-ss showed rapid and transient induction of Egr-1.

Rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through peroxisome proliferator-activated receptor-gamma.

The nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, originally identified as a key mediator of adipogenesis, is expressed widely and implicated in diverse biological responses. Both natural and synthetic agonists of PPAR-gamma abrogated the stimulation of collagen synthesis and myofibroblast differentiation induced by transforming growth factor (TGF)-beta in vitro. To characterize the role of PPAR-gamma in the fibrotic process in vivo, the synthetic agonist rosiglitazone was used in a mouse model of scleroderma.