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J. Biol. Chem., Vol. 275, Issue 36, 27566-27575, September 8, 2000
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From the 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
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 A4
(LXA4), namely inhibition of leukotriene D4 (LTD4)-induced human renal mesangial
cell proliferation, and investigate the signal transduction
mechanisms involved. LXA4 blocked
LTD4-stimulated phosphatidylinositol 3-kinase (PI 3-kinase) activity in parallel to inhibition of LTD4-induced
mesangial cell proliferation. Screening of a human mesangial
cell cDNA library revealed expression of the recently described
cys-leukotriene1/LTD4 receptor.
LTD4-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. LTD4-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 LXA4 receptor. In contrast to LTD4,
LXA4 showed differential activation of erk and p38.
LXA4 activation of erk was insensitive to PTX and PI
3-kinase inhibition, whereas LXA4 activation of p38 was sensitive to PTX and could be blocked by the LTD4 receptor
antagonist SKF 104353. These data suggest that LXA4
stimulation of the MAP kinase superfamily involves two distinct
receptors: one shared with LTD4 and coupled to a
PTX-sensitive G protein (Gi) and a second coupled via an
alternative G protein, such as Gq or G12, to
erk activation. These data expand on the spectrum of LXA4
bioactions within an inflammatory milieu.
Lipoxin A4 Antagonizes the Mitogenic Effects of
Leukotriene D4 in Human Renal Mesangial Cells
DIFFERENTIAL ACTIVATION OF MAP KINASES THROUGH DISTINCT
RECEPTORS*
,
*
This work was funded by grants from The Health Research
Board, Forbairt (Enterprise Ireland), and The Wellcome Trust.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Current address: Imperial Cancer Research Fund Medical
Oncology Unit, Western General Hospital National Health Service Trust, Edinburgh EH4 2XU, United Kingdom.
§
Current address: Sir Patrick Dun's Research Laboratories, Trinity
College Medical School, St. James Hospital, Dublin 8, Ireland.
¶
To whom correspondence should be addressed. Tel.:
353-1-803-2188; Fax: 353-1-830-8404; E-mail: cgodson@mater.ie.
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