title: A central role for the JNK pathway in mediating the antagonistic activity of pro-inflammatory cytokines against transforming growth factor-beta-driven SMAD3/4-specific gene expression.
abstract: We have focused our attention on the molecular events underlying the antagonistic activities of pro-inflammatory cytokines against transforming growth factor-beta (TGF-beta)/SMAD signaling. Using jnk1/2-knockout (jnk(-/-)) and I kappa B kinase-gamma/nemo(-/-) fibroblasts, we have determined the specific roles played by the JNK/AP-1 and NF-kappa B/Rel pathways in this phenomenon. We demonstrate that, in a cellular context devoid of JNK activity (i.e. jnk(-/-) fibroblasts), interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) did not inhibit the formation of SMAD-DNA complexes and the resulting SMAD-driven transcription in response to TGF-beta. On the other hand, lack of NF-kappa B activity in nemo(-/-) fibroblasts did not affect the antagonistic effect of pro-inflammatory cytokines against TGF-beta. In the latter cell type, overexpression of antisense c-jun mRNA or of a dominant-negative form of MKK4 blocked the inhibitory activity of TNF-alpha, similar to what was observed in normal human dermal fibroblasts. Among JNK substrates, c-Jun and JunB (but not activating transcription factor-2) antagonized TGF-beta/SMAD signaling in a JNK-dependent manner. Overexpression of JNK1 in jnk(-/-) fibroblasts restored the ability of cytokines and Jun proteins to interfere with SMAD signaling. In junAA mouse embryo fibroblasts, in which c-Jun can no longer be phosphorylated by JNK, JunB substituted for c-Jun in mediating the cytokine effect against SMAD-driven transcription in a JNK-dependent manner. These results suggest a critical role for JNK-mediated c-Jun and JunB phosphorylation in transmitting the inhibitory effect of pro-inflammatory cytokines against TGF-beta-induced SMAD signaling. In addition, we demonstrate that such a JNK-dependent regulatory mechanism underlies the antagonistic activity of TNF-alpha against TGF-beta-induced up-regulation of type I and III collagens in fibroblasts.
authors.affiliation: INSERM U532, Institut de Recherche sur la Peau Hôpital Saint-Louis, 75475 Paris Cedex 10, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Verrecchia
authors.forename: Charlotte
authors.initials: C
authors.lastname: Tacheau
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D016207:Cytokines / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D018836:Inflammation Mediators / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases