The volatile anesthetics halothane and isoflurane differentially modulate proinflammatory cytokine-induced p38 mitogen-activated protein kinase activation.
OBJECTIVE
Volatile anesthetics affect the cardiovascular and immune systems. Toward a better understanding of the molecular mechanisms behind the modulation exerted by these agents, we focused on the effects of halothane and isoflurane on the activation of p38 mitogen-activated protein kinase (MAPK), which plays a critical role in the cellular responses to extracellular stimuli such as lipopolysaccharide (LPS) and proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin 1 (IL-1).


METHODS
Human umbilical vein endothelial cells and HeLa cells, an established cell line, were examined by molecular biological methods. Cells were treated with proinflammatory compounds with or without the volatile anesthetics. p38 MAPK activation was investigated by Western blotting analysis with phosphospecific anti-p38 MAPK antibodies.


RESULTS
Isoflurane activated p38 MAPK by itself, but halothane did not. Halothane or isoflurane augmented the LPS- and TNF-induced activation of p38 MAPK. In contrast, neither halothane nor isoflurane enhanced the p38 MAPK activation induced by IL-1. Neither of the anesthetics affected H(2)O(2) or MAPK kinase 3 (MKK3)-induced p38 MAPK activation.


CONCLUSIONS
Our in vitro results indicate that the volatile anesthetics used in the clinical field and in animal experiments modify the p38 MAPK signaling cascade and suggest that the target molecules of the anesthetics are not unique and the anesthetics regulate them differentially at clinically relevant doses.
Itoh
Tatsuya
T
Department of Anesthesia, Kyoto University Hospital, Kyoto University, Kyoto, Japan.
Hirota
Kiichi
K
Hisano
Taizo
T
Namba
Tsunehisa
T
Fukuda
Kazuhiko
K
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006221:Halothane / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D048371:MAP Kinase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D018685:Anesthetics, Inhalation; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D007530:Isoflurane; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D006221:Halothane