Propanil inhibits tumor necrosis factor-alpha production by reducing nuclear levels of the transcription factor nuclear factor-kappab in the macrophage cell line ic-21.

Tumor necrosis factor-alpha (TNF-alpha) is an essential proinflammatory cytokine whose production is normally stimulated by bacterial cell wall components, such as lipopolysaccharide (LPS), during an infection. Macrophages stimulated with LPS in vitro produce several cytokines, including TNF-alpha. LPS-stimulated primary mouse macrophages produced less TNF-alpha protein and message after treatment with the herbicide propanil (Xie et al., Toxicol. Appl. Pharmacol. 145, 184-191, 1997). Nuclear factor-kappaB (NF-kappaB) tightly regulates TNF-alpha transcription. Therefore, as a step toward understanding the mechanism of the effect of propanil on TNF-alpha transcription, IC-21 cells were transfected with a TNF-alpha promoter-luciferase construct, and the effect of propanil on luciferase activity was measured. Cells transfected with promoter constructs containing a kappaB site showed decreased luciferase activity relative to controls after propanil treatment. These observations implicated NF-kappaB binding as an intracellular target of propanil. Further studies demonstrated a marked reduction in the nuclear levels of the stimulatory p65 subunit of NF-kappaB after propanil treatment, as measured by fluorescence confocal microscopy and Western blot analysis. The p50 subunit of NF-kappaB was not found to be reduced after propanil exposure by Western blot. Electrophoretic mobility gel shift assays showed decreased DNA binding of both p65/p50 heterodimers and p50/p50 homodimers to the kappaB3 site of the TNF-alpha promoter of propanil-treated cells. The marked reduction in nuclear p65/p50 NF-kappaB levels and diminished binding to the TNF-alpha promoter in propanil-treated cells are consistent with reduced TNF-alpha levels induced by LPS.

Frost LL ，Neeley YX ，Schafer R ，Gibson LF ，Barnett JB ... -  《TOXICOLOGY AND APPLIED PHARMACOLOGY》

Molecular mechanisms underlying mancozeb-induced inhibition of TNF-alpha production.

Corsini E ，Viviani B ，Birindelli S ，Gilardi F ，Torri A ，Codecà I ，Lucchi L ，Bartesaghi S ，Galli CL ，Marinovich M ，Colosio C ... -  《TOXICOLOGY AND APPLIED PHARMACOLOGY》

Regulation of intercellular adhesion molecule-1 gene by tumor necrosis factor-alpha is mediated by the nuclear factor-kappaB heterodimers p65/p65 and p65/c-Rel in the absence of p50.

Aoudjit F ，Brochu N ，Bélanger B ，Stratowa C ，Hiscott J ，Audette M ... -  《-》

Responses to the proinflammatory cytokines interleukin-1 and tumor necrosis factor alpha in cells derived from rheumatoid synovium and other joint tissues involve nuclear factor kappaB-mediated induction of the Ets transcription factor ESE-1.

Grall F ，Gu X ，Tan L ，Cho JY ，Inan MS ，Pettit AR ，Thamrongsak U ，Choy BK ，Manning C ，Akbarali Y ，Zerbini L ，Rudders S ，Goldring SR ，Gravallese EM ，Oettgen P ，Goldring MB ，Libermann TA ... -  《ARTHRITIS AND RHEUMATISM》

Activation of the adenosine A3 receptor in RAW 264.7 cells inhibits lipopolysaccharide-stimulated tumor necrosis factor-alpha release by reducing calcium-dependent activation of nuclear factor-kappaB and extracellular signal-regulated kinase 1/2.

Martin L ，Pingle SC ，Hallam DM ，Rybak LP ，Ramkumar V ... -  《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》