Lipoxin A4 antagonizes the mitogenic effects of leukotriene D4 in human renal mesangial cells. Differential activation of MAP kinases through distinct receptors.
The lipoxygenase-derived eicosanoids leukotrienes and lipoxins are well defined regulators of hemeodynamics and leukocyte recruitment in inflammatory conditions. Here, we describe a novel bioaction of lipoxin A(4) (LXA(4)), namely inhibition of leukotriene D(4) (LTD(4))-induced human renal mesangial cell proliferation, and investigate the signal transduction mechanisms involved. LXA(4) blocked LTD(4)-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity in parallel to inhibition of LTD(4)-induced mesangial cell proliferation. Screening of a human mesangial cell cDNA library revealed expression of the recently described cys-leukotriene(1)/LTD(4) receptor. LTD(4)-induced mesangial cell proliferation required both extracellular-related signal regulated kinase (erk) and PI 3-kinase activation and may involve platelet-derived growth factor receptor transactivation. LTD(4)-stimulated the MAP kinases erk and p38 via a pertussis toxin (PTX)-sensitive pathway dependent on PI 3-kinase and protein kinase C activation. On screening a cDNA library, mesangial cells were found to express the previously described LXA(4) receptor. In contrast to LTD(4), LXA(4) showed differential activation of erk and p38. LXA(4) activation of erk was insensitive to PTX and PI 3-kinase inhibition, whereas LXA(4) activation of p38 was sensitive to PTX and could be blocked by the LTD(4) receptor antagonist SKF 104353. These data suggest that LXA(4) stimulation of the MAP kinase superfamily involves two distinct receptors: one shared with LTD(4) and coupled to a PTX-sensitive G protein (G(i)) and a second coupled via an alternative G protein, such as G(q) or G(12), to erk activation. These data expand on the spectrum of LXA(4) bioactions within an inflammatory milieu.
McMahon
B
B
Centre for Molecular Inflammation and Vascular Research, Department of Medicine and Therapeutics, Mater Misericordiae Hospital and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, 41 Eccles St., Dublin 7, Ireland.
Stenson
C
C
McPhillips
F
F
Fanning
A
A
Brady
H R
HR
Godson
C
C
D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D004789:Enzyme Activation; D015723:Gene Library; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D044045:Lipoxins; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D044042:Receptors, Formyl Peptide; D018077:Receptors, Leukotriene / Q000235:genetics / Q000502:physiology*; D044067:Receptors, Lipoxin; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects; D013539:Simian virus 40 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases
C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D018077:Receptors, Leukotriene; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C083169:leukotriene D4 receptor