TY - JOUR
T1 - Leukotriene B4 stimulates Rac-ERK cascade to generate reactive oxygen species that mediates chemotaxis
AU - Woo, Chang Hoon
AU - You, Hye Jin
AU - Cho, Sung Hoon
AU - Eom, Young Woo
AU - Chun, Jang Soo
AU - Yoo, Yung Joon
AU - Kim, Jae Hong
PY - 2002/3/8
Y1 - 2002/3/8
N2 - Leukotriene B4 is a potent chemoattractant known to be involved mainly in inflammation, immune responses, and host defense against infection, although the exact signaling mechanisms by which it exerts its effects are not well understood. Here we show that exogenous leukotriene B4 induces reactive oxygen species (ROS) generation via a Rac-dependent pathway, and that stable expression of RacN17, a dominant negative Rac1 mutant, completely blocks leukotriene B4-induced ROS generation. In addition, leukotriene B4-induced ROS generation is selectively blocked by inhibition of ERK or cytosolic phospholipase A2, but not p38 kinase, which is indicative of its dependence on ERK activation and synthesis of arachidonic acid. Consistent with those findings, leukotriene B4 Rac-dependently stimulates ERK and cytosolic phospholipase A2 activity, and transient transfection with plasmid expressing RacV12, a constitutively activated Racl mutant, also dose-dependently stimulates ERK activity. Our findings suggest that ERK and cytosolic phospholipase A2 are situated downstream of Rac, and we conclude that Rac, ERK, and cytosolic phospholipase A2 all play pivotal roles in mediating the ROS generation that appears to be a prerequisite for leukotriene B4-induced chemotaxis and cell proliferation.
AB - Leukotriene B4 is a potent chemoattractant known to be involved mainly in inflammation, immune responses, and host defense against infection, although the exact signaling mechanisms by which it exerts its effects are not well understood. Here we show that exogenous leukotriene B4 induces reactive oxygen species (ROS) generation via a Rac-dependent pathway, and that stable expression of RacN17, a dominant negative Rac1 mutant, completely blocks leukotriene B4-induced ROS generation. In addition, leukotriene B4-induced ROS generation is selectively blocked by inhibition of ERK or cytosolic phospholipase A2, but not p38 kinase, which is indicative of its dependence on ERK activation and synthesis of arachidonic acid. Consistent with those findings, leukotriene B4 Rac-dependently stimulates ERK and cytosolic phospholipase A2 activity, and transient transfection with plasmid expressing RacV12, a constitutively activated Racl mutant, also dose-dependently stimulates ERK activity. Our findings suggest that ERK and cytosolic phospholipase A2 are situated downstream of Rac, and we conclude that Rac, ERK, and cytosolic phospholipase A2 all play pivotal roles in mediating the ROS generation that appears to be a prerequisite for leukotriene B4-induced chemotaxis and cell proliferation.
UR - http://www.scopus.com/inward/record.url?scp=0037040973&partnerID=8YFLogxK
U2 - 10.1074/jbc.M104766200
DO - 10.1074/jbc.M104766200
M3 - Article
C2 - 11756405
AN - SCOPUS:0037040973
SN - 0021-9258
VL - 277
SP - 8572
EP - 8578
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -