Transcriptional interactions of transforming growth-factor-beta with pro-inflammatory cytokines.
BACKGROUND
Inflammation and tissue injury are characterized by a massive infiltration of mononuclear cells. These pro-inflammatory cells, which are the precursors of an inflammatory response by the immune system, secrete a variety of cytokines and growth factors that alter the biosynthetic repertoire of the resident connective tissue cells. Specifically, expression of connective tissue matrix metalloproteinases, such as stromelysin and interstitial collagenase, is enhanced, together with the expression of chemoattractants for leukocytes, such as interleukin-8 (IL-8). These events lead to increased connective tissue degradation. We have examined the growth factor regulation of expression in cultured fibroblasts of the prototypic pro-inflammatory factors interstitial collagenase and IL-8.


RESULTS
We demonstrate that transforming growth factor-beta (TGF-beta) does not interfere with cytokine-induced IL-8 gene expression, nor does it affect the activity of NF-kappaB-driven promoters. In contrast, TGF-beta down-regulates collagenase gene expression through the induction of the jun-B proto-oncogene. Jun-B is a negative regulator of c-jun, which mediates cytokine activation of collagenase gene expression through its action as a component of the AP-1 transcription factor.


CONCLUSIONS
Our data suggest that TGF-beta may attenuate the deleterious events that occur in inflammation by preventing cytokine-induced extracellular matrix degradation, although it does not affect cytokine-induced recruitment of pro-inflammatory cells. Furthermore, our data suggest a potential therapeutic use for jun-B, which may be a candidate for gene therapy in disease states that are characterized by excessive connective tissue degradation.
Mauviel
A
A
Department of Dermatology, Jefferson Medical College, Section of Molecular Dermatology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Qiu Chen
Y
Y
Dong
W
W
Evans
C H
CH
Uitto
J
J