Disruption of the actin cytoskeleton results in nuclear factor-kappaB activation and inflammatory mediator production in cultured human intestinal epithelial cells.
The cytoskeleton in eukaryotic cells is composed of two major filament systems, the microtubule system and the actin cytoskeleton. The microtubule system has recently emerged as an important regulator of NF-kappaB function. However, the role that the actin microfilament system plays in controlling NF-kappaB activation is incompletely understood. In this study, we examined the effect of actin cytoskeleton disruption on NF-kappaB activation in human intestinal epithelial cells. Treatment of HT-29 or Caco-2 cells with the prototypic actin disrupting agents cytochalasin D or latrunculin B resulted in increased NF-kappaB DNA binding and NF-kappaB-dependent transcriptional activity. This NF-kappaB activation by cytochalasin D was secondary to an effect on IkappaB, because cytochalasin D-induced IkappaB degradation and the cytochalasin D-induced increase in NF-kappaB-dependent transcriptional activity was prevented by a dominant negative IkappaB mutant. Exposure of the cells to cytochalasins or latrunculin B increased gene expression and release of the NF-kappaB-dependent chemokines IL-8 and GRO-alpha. Cytochalasin D also activated p38 MAP kinase, which pathway contributed to the cytochalasin D-induced increase in IL-8 production. These results demonstrate that the actin cytoskeleton plays an important role in the regulation of NF-kappaB activation and inflammatory events in intestinal epithelial cells.
Németh
Zoltán H
ZH
Department of Surgery, UMD NJ-New Jersey Medical School, Newark, New Jersey 07103, USA.
Deitch
Edwin A
EA
Davidson
Marson T
MT
Szabó
Csaba
C
Vizi
E Sylvester
ES
Haskó
György
G
D000199:Actins / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D016209:Interleukin-8 / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D014158:Transcription, Genetic / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D013844:Thiazoles; D053778:Thiazolidines; D015638:Cytochalasin D; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C037068:latrunculin B