Clostridium perfringens alpha-toxin induces the release of IL-8 through a dual pathway via TrkA in A549 cells.
A characteristic feature of gas gangrene with Clostridium perfringens (C. perfringens) is the absence of neutrophils within the infected area and the massive accumulation of neutrophils at the vascular endothelium around the margins of the necrotic region. Intravenous injection of C. perfringens alpha-toxin into mice resulted in the accumulation of neutrophils at the vascular endothelium in lung and liver, and release of GRO/KC, a member of the CXC chemokine family with homology to human interleukin-8 (IL-8). Alpha-toxin triggered activation of signal transduction pathways causing mRNA expression and production of IL-8, which activates migration and binding of neutrophils, in A549 cells. K252a, a tyrosine kinase A (TrkA) inhibitor, and siRNA for TrkA inhibited the toxin-induced phosphorylation of TrkA and production of IL-8. In addition, K252a inhibited the toxin-induced phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). PD98059, an ERK1/2 inhibitor, depressed phosphorylation of ERK1/2 and nuclear translocation of nuclear factor kappa B (NF-κB) p65, but SB203580, a p38 MAPK inhibitor, did not. On the other hand, PD98059 and SB203580 suppressed the toxin-induced production of IL-8. Treatment of the cells with PD98059 resulted in inhibition of IL-8 mRNA expression induced by the toxin and that with SB203580 led to a decrease in the stabilization of IL-8 mRNA. These results suggest that alpha-toxin induces production of IL-8 through the activation of two separate pathways, the ERK1/2/NF-κB and p38 MAPK pathways.
Department of Microbiology, Tokushima Bunri University, Yamashiro-cho, Tokushima, Japan. masa@ph.bunri-u.ac.jp
Masataka
M
Oda
Ryota
R
Shiihara
Yuka
Y
Ohmae
Michiko
M
Kabura
Teruhisa
T
Takagishi
Keiko
K
Kobayashi
Masahiro
M
Nagahama
Masahisa
M
Inoue
Tomomi
T
Abe
Koujun
K
Setsu
Jun
J
Sakurai
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D010738:Type C Phospholipases / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D002227:Carbazoles; D026121:Indole Alkaloids; D016209:Interleukin-8; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C049985:staurosporine aglycone; D011505:Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; C040649:alpha toxin, Clostridium perfringens