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pubmed:abstractText |
We used a gene knockout approach to elucidate the specific roles played by the Jun-N-terminal kinase (JNK) and NF-kappaB pathways downstream of TNF-alpha in the context of alpha(2) type I collagen gene (COL1A2) expression. In JNK1-/--JNK2-/- (JNK-/-) fibroblasts, TNF-alpha inhibited basal COL1A2 expression but had no effect on TGF-beta-driven gene transactivation unless jnk1 was introduced ectopically. Conversely, in NF-kappaB essential modulator-/- (NEMO-/-) fibroblasts, lack of NF-kappaB activation did not influence the antagonism exerted by TNF-alpha against TGF-beta but prevented repression of basal COL1A2 gene expression. Similar regulatory mechanisms take place in dermal fibroblasts, as evidenced using transfected dominant-negative forms of MKK4 and IKK-alpha, critical kinases upstream of the JNK and NF-kappaB pathways, respectively. These results represent the first demonstration of an alternate usage of distinct signaling pathways by TNF-alpha to inhibit the expression of a given gene, COL1A2, depending on its activation state.
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pubmed:affiliation |
INSERM U532, Institut de Recherche sur la Peau, Hôpital Saint-Louis, Pavillon Bazin, 75010 Paris, France.
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