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The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells

The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells
The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells
Activated mast cells are a major source of the eicosanoids PGD(2) and leukotriene C(4) (LTC(4)), which contribute to allergic responses. These eicosanoids are produced following the ERK1/2-dependent activation of cytosolic phospholipase A(2), thus liberating arachidonic acid, which is subsequently metabolized by the actions of 5-lipoxygenase and cyclooxygenase to form LTC(4) and PGD(2), respectively. These pathways also generate reactive oxygen species (ROS), which have been proposed to contribute to FcepsilonRI-mediated signaling in mast cells. In this study, we demonstrate that, in addition to ERK1/2-dependent pathways, ERK1/2-independent pathways also regulate FcepsilonRI-mediated eicosanoid and ROS production in mast cells. A role for the Tec kinase Btk in the ERK1/2-independent regulatory pathway was revealed by the significantly attenuated FcepsilonRI-dependent PGD(2), LTC(4), and ROS production in bone marrow-derived mast cells of Btk(-/-) mice. The FcepsilonRI-dependent activation of Btk and eicosanoid and ROS generation in bone marrow-derived mast cells and human mast cells were similarly blocked by the PI3K inhibitors, Wortmannin and LY294002, indicating that Btk-regulated eicosanoid and ROS production occurs downstream of PI3K. In contrast to ERK1/2, the PI3K/Btk pathway does not regulate cytosolic phospholipase A(2) phosphorylation but rather appears to regulate the generation of ROS, LTC(4), and PGD(2) by contributing to the necessary Ca(2+) signal for the production of these molecules. These data demonstrate that strategies to decrease mast cell production of ROS and eicosanoids would have to target both ERK1/2- and PI3K/Btk-dependent pathways.
0022-1767
7706-7712
Kuehn, Hye Sun
a0dd86b6-a26b-463a-8815-ca6365cb88b1
Swindle, Emily J.
fe393c7a-a513-4de4-b02e-27369bd7e84f
Kim, Mi-Sun
f6a05fb0-72c4-481e-8c85-cefb57af85cd
Beaven, Michael A.
0b487010-0c47-45cd-89a2-7a597d6544fa
Metcalfe, Dean D.
af82a41c-70b6-4245-801f-e4fab629bb3c
Gilfillan, Alasdair M.
a1220b14-3ff9-46bd-9ecb-13abc10c53b2
Kuehn, Hye Sun
a0dd86b6-a26b-463a-8815-ca6365cb88b1
Swindle, Emily J.
fe393c7a-a513-4de4-b02e-27369bd7e84f
Kim, Mi-Sun
f6a05fb0-72c4-481e-8c85-cefb57af85cd
Beaven, Michael A.
0b487010-0c47-45cd-89a2-7a597d6544fa
Metcalfe, Dean D.
af82a41c-70b6-4245-801f-e4fab629bb3c
Gilfillan, Alasdair M.
a1220b14-3ff9-46bd-9ecb-13abc10c53b2

Kuehn, Hye Sun, Swindle, Emily J., Kim, Mi-Sun, Beaven, Michael A., Metcalfe, Dean D. and Gilfillan, Alasdair M. (2008) The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells. Journal of Immunology, 181 (11), 7706-7712. (PMID:19017959)

Record type: Article

Abstract

Activated mast cells are a major source of the eicosanoids PGD(2) and leukotriene C(4) (LTC(4)), which contribute to allergic responses. These eicosanoids are produced following the ERK1/2-dependent activation of cytosolic phospholipase A(2), thus liberating arachidonic acid, which is subsequently metabolized by the actions of 5-lipoxygenase and cyclooxygenase to form LTC(4) and PGD(2), respectively. These pathways also generate reactive oxygen species (ROS), which have been proposed to contribute to FcepsilonRI-mediated signaling in mast cells. In this study, we demonstrate that, in addition to ERK1/2-dependent pathways, ERK1/2-independent pathways also regulate FcepsilonRI-mediated eicosanoid and ROS production in mast cells. A role for the Tec kinase Btk in the ERK1/2-independent regulatory pathway was revealed by the significantly attenuated FcepsilonRI-dependent PGD(2), LTC(4), and ROS production in bone marrow-derived mast cells of Btk(-/-) mice. The FcepsilonRI-dependent activation of Btk and eicosanoid and ROS generation in bone marrow-derived mast cells and human mast cells were similarly blocked by the PI3K inhibitors, Wortmannin and LY294002, indicating that Btk-regulated eicosanoid and ROS production occurs downstream of PI3K. In contrast to ERK1/2, the PI3K/Btk pathway does not regulate cytosolic phospholipase A(2) phosphorylation but rather appears to regulate the generation of ROS, LTC(4), and PGD(2) by contributing to the necessary Ca(2+) signal for the production of these molecules. These data demonstrate that strategies to decrease mast cell production of ROS and eicosanoids would have to target both ERK1/2- and PI3K/Btk-dependent pathways.

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Published date: 1 December 2008
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 350561
URI: http://eprints.soton.ac.uk/id/eprint/350561
ISSN: 0022-1767
PURE UUID: 229d5424-6612-474a-927d-564b6c9e7e64
ORCID for Emily J. Swindle: ORCID iD orcid.org/0000-0003-3644-7747

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Date deposited: 04 Apr 2013 14:56
Last modified: 18 Feb 2021 17:13

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Contributors

Author: Hye Sun Kuehn
Author: Mi-Sun Kim
Author: Michael A. Beaven
Author: Dean D. Metcalfe
Author: Alasdair M. Gilfillan

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