Antifibrotic therapy in scleroderma: extracellular or intracellular targeting of activated fibroblasts?
Therapeutic anticytokine approaches have revolutionized the treatment of chronic inflammatory diseases, and targeting of transforming growth factor-beta (TGF-beta), a key factor in the pathogenesis of fibrosis, is undergoing evaluation for scleroderma. Several considerations dictate a cautious approach to anti-TGF-beta interventions. These include the possibility of multiple cytokines having overlapping roles in the pathogenesis of fibrosis and concerns that, in light of its numerous homeostatic functions, blocking TGF-beta may have serious adverse consequences. Furthermore, as autonomously activated cells, scleroderma fibroblasts may be unresponsive to blockade of TGF-beta signaling. This article reviews the experimental evidence underlying these concerns, and indicates rational approaches to addressing and overcoming them.
Varga
John
J
Section of Rheumatology (M/C 733), University of Illinois College of Medicine, Room 1158, Molecular Biology Research Building, 900 South Ashland Avenue, Chicago, IL 60607, USA. jvarga@uic.edu
D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D008233:Lymphotoxin-alpha / Q000037:antagonists & inhibitors*; D012595:Scleroderma, Systemic / Q000503:physiopathology* / Q000628:therapy*; D015398:Signal Transduction / Q000502:physiology*
D008233:Lymphotoxin-alpha