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Article ; Online: Regulation of Discrete Functional Responses by Syk and Src Family Tyrosine Kinases in Human Neutrophils.

Ear, Thornin / Tatsiy, Olga / Allard, Frédérick L / McDonald, Patrick P

2017 Volume 2017, Page(s) 4347121

Abstract: Neutrophils play a critical role in innate immunity and also influence adaptive immune responses. This occurs in good part through their production of inflammatory and immunomodulatory cytokines, in conjunction with their prolonged survival at inflamed ... ...

Abstract	Neutrophils play a critical role in innate immunity and also influence adaptive immune responses. This occurs in good part through their production of inflammatory and immunomodulatory cytokines, in conjunction with their prolonged survival at inflamed foci. While a picture of the signaling machinery underlying these neutrophil responses is now emerging, much remains to be uncovered. In this study, we report that neutrophils constitutively express various Src family isoforms (STKs), as well as Syk, and that inhibition of these protein tyrosine kinases selectively hinders inflammatory cytokine generation by acting posttranscriptionally. Accordingly, STK or Syk inhibition decreases the phosphorylation of signaling intermediates (e.g., eIF-4E, S6K, and MNK1) involved in translational control. By contrast, delayed apoptosis appears to be independent of either STKs or Syk. Our data therefore significantly extend our understanding of which neutrophil responses are governed by STKs and Syk and pinpoint some signaling intermediates that are likely involved. In view of the foremost role of neutrophils in several chronic inflammatory conditions, our findings identify potential molecular targets that could be exploited for future therapeutic intervention.
Language	English
Publishing date	2017
Publishing country	Egypt
Document type	Journal Article
ZDB-ID	2817541-4
ISSN	2314-7156 ; 2314-8861
ISSN (online)	2314-7156
ISSN	2314-8861
DOI	10.1155/2017/4347121
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Article ; Online: MEK-independent ERK activation in human neutrophils and its impact on functional responses.

Simard, François A / Cloutier, Alexandre / Ear, Thornin / Vardhan, Harsh / McDonald, Patrick P

Journal of leukocyte biology

2015 Volume 98, Issue 4, Page(s) 565–573

Abstract: Neutrophils influence innate and adaptative immunity, notably through the generation of numerous cytokines and chemokines and through the modulation of their constitutive apoptosis. Several signaling cascades are known to control neutrophil responses, ... ...

Abstract	Neutrophils influence innate and adaptative immunity, notably through the generation of numerous cytokines and chemokines and through the modulation of their constitutive apoptosis. Several signaling cascades are known to control neutrophil responses, including the MEK pathway, which is normally coupled to ERK. However, we show here that in human neutrophils stimulated with cytokines or TLR ligands, MEK and ERK are activated independently of each other. Pharmacological blockade of MEK had no effect on the induction of ERK kinase activity and vice versa. In autologous PBMC exposed to the same stimuli or in neutrophils exposed to chemoattractants, this uncoupling of MEK and ERK was not observed. Whereas we had shown before that MEK inhibition impairs cytokine generation translationally in LPS- or TNF-stimulated neutrophils, ERK inhibition affected this response transcriptionally and translationally. Transcriptional targets or ERK include the mitogen- and stress-activated protein kinase 1 (MSK-1) and its substrates, C/EBPβ and CREB, whereas translational targets include the S6 kinase and its substrate, the S6 ribosomal protein. In addition to affecting cytokine production, ERK inhibition interfered with how LPS or TNF promotes neutrophil survival and levels of the myeloid cell leukemia 1 (Mcl-1) antiapoptotic protein. Whereas the ERK-activating kinase was not identified, we found that the MAP3K, TGF-β-activated kinase 1 (TAK1), acts upstream of ERK and MEK in neutrophils. Our results document a functional uncoupling of the MEK/ERK module under certain stimulatory conditions and suggest that therapeutic strategies based on MEK inhibition might benefit from being complemented by ERK inhibition, particularly in chronic inflammatory conditions featuring a strong neutrophilic component.
MeSH term(s)	Apoptosis/immunology ; Enzyme Activation/immunology ; Enzyme-Linked Immunosorbent Assay ; Extracellular Signal-Regulated MAP Kinases/immunology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flow Cytometry ; Humans ; Immunoblotting ; Immunoprecipitation ; MAP Kinase Kinase Kinases/immunology ; MAP Kinase Kinase Kinases/metabolism ; MAP Kinase Signaling System/immunology ; Neutrophils/immunology ; Neutrophils/metabolism ; Real-Time Polymerase Chain Reaction
Chemical Substances	Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinases (EC 2.7.11.25)
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1189/jlb.2MA1214-599R
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Article ; Online: Autocrine role of endogenous interleukin-18 on inflammatory cytokine generation by human neutrophils.

Fortin, Carl F / Ear, Thornin / McDonald, Patrick P

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2009 Volume 23, Issue 1, Page(s) 194–203

Abstract: Neutrophils are key players of innate immunity and influence inflammatory and immune reactions through the production of numerous cytokines. Interleukin-18 (IL-18) is known to stimulate several neutrophil responses, and recent evidence suggests that ... ...

Abstract	Neutrophils are key players of innate immunity and influence inflammatory and immune reactions through the production of numerous cytokines. Interleukin-18 (IL-18) is known to stimulate several neutrophil responses, and recent evidence suggests that neutrophils might represent a source of IL-18. Here, we show that neutrophils constitutively produce both IL-18 and its antagonist, IL-18BP. Cell activation does not affect IL-18BP release but leads to an increased gene expression and secretion of IL-18, a process that depends on NF-kappaB activation. Moreover, endogenous IL-18 feeds back on the neutrophils to augment cytokine generation in lipopolysaccharide-treated cells. Accordingly, exogenous IL-18 can induce the gene expression and release of several inflammatory cytokines in neutrophils, including its own expression. We finally report that IL-18 activates the p38 MAPK, MEK/ERK, and PI3K/Akt pathways in neutrophils. The IKK cascade is also activated by IL-18, resulting in IkappaB-alpha degradation, NF-kappaB activation, and RelA phosphorylation. Accordingly, these pathways contribute to the generation of inflammatory cytokines in IL-18-stimulated neutrophils. By contrast, the phosphorylation and DNA-binding activity of various STAT proteins were not induced by IL-18. Collectively, our results unveil new interactions between IL-18 and neutrophils and further support a role for these cells in influencing both innate and adaptive immunity.
MeSH term(s)	Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression Regulation/physiology ; Humans ; I-kappa B Kinase/metabolism ; Inflammation/metabolism ; Intercellular Signaling Peptides and Proteins/metabolism ; Interleukin-18/metabolism ; NF-kappa B/metabolism ; Neutrophils/metabolism ; Oncogene Protein v-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction ; Time Factors ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	Intercellular Signaling Peptides and Proteins ; Interleukin-18 ; NF-kappa B ; interleukin-18 binding protein ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Oncogene Protein v-akt (EC 2.7.11.1) ; I-kappa B Kinase (EC 2.7.11.10) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2009-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.08-110213
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Article ; Online: Cytokine generation, promoter activation, and oxidant-independent NF-kappaB activation in a transfectable human neutrophilic cellular model.

Ear, Thornin / McDonald, Patrick P

BMC immunology

2008 Volume 9, Page(s) 14

Abstract: Background: Human neutrophils are key players of innate immunity, and influence inflammatory and immune reactions through the production of numerous cytokines and chemokines. Despite major advances in our understanding of this important functional ... ...

Abstract	Background: Human neutrophils are key players of innate immunity, and influence inflammatory and immune reactions through the production of numerous cytokines and chemokines. Despite major advances in our understanding of this important functional response of neutrophils, the short lifespan of these cells and their resistance to transfection have always been an obstacle to the detailed dissection of signaling pathways and effector responses that is often possible in other cell types. Results: Here, we report that granulocytic differentiation of human PLB-985 cells with DMSO yields cells that are neutrophil-like with respect to surface markers, acquisition of responsiveness to physiological neutrophil stimuli (fMLP, LPS), cytokine expression and production profile, and transcription factor activation profile (NF-kappaB, C/EBP, AP-1, STAT). We also show that granulocytic PLB-985 cells can be reliably tranfected by nucleofection in a rapid and efficient manner. Indeed, we overexpressed several proteins and luciferase constructs into these cells. In particular, overexpression of a dominant negative IkappaB-alpha confirmed the central role of NF-kappaB in the production of cytokines by granulocytes. Moreover, the use of PLB-985 granulocytes in which the NADPH oxidase is inactive due to the targeted disruption of a key component (gp91phox) revealed that NF-kappaB activation and kappaB-dependent responses are independent of endogenous reactive oxygen intermediates in these cells. Antioxidant studies performed in primary human neutrophils support this conclusion. Conclusion: Our results unveil a new facet of the NF-kappaB system of human granulocytes, and pave the way for deciphering signal transduction pathways and promoter activation in these cells.
MeSH term(s)	Cell Differentiation ; Cytokines/biosynthesis ; Flow Cytometry ; Granulocytes/cytology ; Humans ; Models, Biological ; NF-kappa B/metabolism ; Neutrophils/cytology ; Neutrophils/metabolism ; Oxidants ; Promoter Regions, Genetic ; Transfection
Chemical Substances	Cytokines ; NF-kappa B ; Oxidants
Language	English
Publishing date	2008-04-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2172
ISSN (online)	1471-2172
DOI	10.1186/1471-2172-9-14
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Article ; Online: Cytokine generation, promoter activation, and oxidant-independent NF-κB activation in a transfectable human neutrophilic cellular model

McDonald Patrick P / Ear Thornin

BMC Immunology, Vol 9, Iss 1, p

2008 Volume 14

Abstract: Abstract Background Human neutrophils are key players of innate immunity, and influence inflammatory and immune reactions through the production of numerous cytokines and chemokines. Despite major advances in our understanding of this important ... ...

Abstract	Abstract Background Human neutrophils are key players of innate immunity, and influence inflammatory and immune reactions through the production of numerous cytokines and chemokines. Despite major advances in our understanding of this important functional response of neutrophils, the short lifespan of these cells and their resistance to transfection have always been an obstacle to the detailed dissection of signaling pathways and effector responses that is often possible in other cell types. Results Here, we report that granulocytic differentiation of human PLB-985 cells with DMSO yields cells that are neutrophil-like with respect to surface markers, acquisition of responsiveness to physiological neutrophil stimuli (fMLP, LPS), cytokine expression and production profile, and transcription factor activation profile (NF-κB, C/EBP, AP-1, STAT). We also show that granulocytic PLB-985 cells can be reliably tranfected by nucleofection in a rapid and efficient manner. Indeed, we overexpressed several proteins and luciferase constructs into these cells. In particular, overexpression of a dominant negative IκB-α confirmed the central role of NF-κB in the production of cytokines by granulocytes. Moreover, the use of PLB-985 granulocytes in which the NADPH oxidase is inactive due to the targeted disruption of a key component (gp91phox) revealed that NF-κB activation and κB-dependent responses are independent of endogenous reactive oxygen intermediates in these cells. Antioxidant studies performed in primary human neutrophils support this conclusion. Conclusion Our results unveil a new facet of the NF-κB system of human granulocytes, and pave the way for deciphering signal transduction pathways and promoter activation in these cells.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Allergy and Immunology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2008-04-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses.

Sylvain-Prévost, Stéphanie / Ear, Thornin / Simard, François A / Fortin, Carl F / Dubois, Claire M / Flamand, Nicolas / McDonald, Patrick P

Journal of immunology (Baltimore, Md. : 1950)

2015 Volume 195, Issue 11, Page(s) 5393–5403

Abstract: The MAP3 kinase, TAK1, is known to act upstream of IKK and MAPK cascades in several cell types, and is typically activated in response to cytokines (e.g., TNF, IL-1) and TLR ligands. In this article, we report that in human neutrophils, TAK1 can also be ... ...

Abstract	The MAP3 kinase, TAK1, is known to act upstream of IKK and MAPK cascades in several cell types, and is typically activated in response to cytokines (e.g., TNF, IL-1) and TLR ligands. In this article, we report that in human neutrophils, TAK1 can also be activated by different classes of inflammatory stimuli, namely, chemoattractants and growth factors. After stimulation with such agents, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the inducible phosphorylation of ERK occurring in response to these stimuli but had little or no effect on that of p38 MAPK or PI3K. Inhibition of TAK1 also impaired MEKK3 (but not MEKK1) activation by fMLF. Moreover, both TAK1 and the MEK/ERK module were found to influence inflammatory cytokine expression and release in fMLF- and GM-CSF-activated neutrophils, whereas the PI3K pathway influenced this response independently of TAK1. Besides cytokine production, other responses were found to be under TAK1 control in neutrophils stimulated with chemoattractants and/or GM-CSF, namely, delayed apoptosis and leukotriene biosynthesis. Our data further emphasize the central role of TAK1 in controlling signaling cascades and functional responses in primary neutrophils, making it a promising target for therapeutic intervention in view of the foremost role of neutrophils in several chronic inflammatory conditions.
MeSH term(s)	Apoptosis/drug effects ; Cells, Cultured ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Humans ; Inflammation/immunology ; Leukotrienes/biosynthesis ; MAP Kinase Kinase Kinase 1/metabolism ; MAP Kinase Kinase Kinase 3/metabolism ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; MAP Kinase Kinase Kinases/metabolism ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/immunology ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Neutrophils/immunology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Zearalenone/analogs & derivatives ; Zearalenone/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism
Chemical Substances	7-oxozeanol ; Leukotrienes ; N-Formylmethionine Leucyl-Phenylalanine (59880-97-6) ; Zearalenone (5W827M159J) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinase 1 (EC 2.7.11.25) ; MAP Kinase Kinase Kinase 3 (EC 2.7.11.25) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP kinase kinase kinase 7 (EC 2.7.11.25) ; MAP3K1 protein, human (EC 2.7.11.25) ; MAP3K3 protein, human (EC 2.7.11.25)
Language	English
Publishing date	2015-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1402752
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Article: Constitutive nuclear expression of the I kappa B kinase complex and its activation in human neutrophils.

Ear, Thornin / Cloutier, Alexandre / McDonald, Patrick P

Journal of immunology (Baltimore, Md. : 1950)

2005 Volume 175, Issue 3, Page(s) 1834–1842

Abstract: A singular feature of human neutrophils is that they constitutively express substantial amounts of NF-kappaB/Rel proteins and IkappaB-alpha in the nucleus. In this study, we show that in these cells, IkappaB kinase alpha (IKKalpha), IKKbeta, and IKKgamma ...

Abstract	A singular feature of human neutrophils is that they constitutively express substantial amounts of NF-kappaB/Rel proteins and IkappaB-alpha in the nucleus. In this study, we show that in these cells, IkappaB kinase alpha (IKKalpha), IKKbeta, and IKKgamma also partially localize to the nucleus, whereas IKK-related kinases (IKKepsilon, TANK-binding kinase-1) are strictly cytoplasmic, and the NF-kappaB-inducing kinase is strictly nuclear. Following neutrophil activation, IKKbeta and IKKgamma become transiently phosphorylated in both the cytoplasm and nucleus, whereas IKKalpha transiently vanishes from both compartments in what appears to be an IKKbeta-dependent process. These responses are paralleled by the degradation of IkappaB-alpha, and by the phosphorylation of RelA on serine 536, in both compartments. Although both proteins can be IKK substrates, inhibition of IKK prevented IkappaB-alpha phosphorylation, while that of RelA was mostly unaffected. Finally, we provide evidence that the nuclear IKK isoforms (alpha, beta, gamma) associate with chromatin following neutrophil activation, which suggests a potential role in gene regulation. This is the first study to document IKK activation and the phosphorylation of NF-kappaB/Rel proteins in primary neutrophils. More importantly, our findings unveil a hitherto unsuspected mode of activation for the IKK/IkappaB signaling cascade within the cell nucleus.
MeSH term(s)	Active Transport, Cell Nucleus/physiology ; Cells, Cultured ; Chromatin/enzymology ; Cytoplasm/enzymology ; Enzyme Activation/genetics ; Humans ; I-kappa B Kinase ; Isoenzymes/biosynthesis ; Isoenzymes/genetics ; Isoenzymes/metabolism ; NF-kappa B/metabolism ; Neutrophil Activation/genetics ; Neutrophils/cytology ; Neutrophils/enzymology ; Neutrophils/metabolism ; Nuclear Proteins/biosynthesis ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/biosynthesis ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Resting Phase, Cell Cycle/physiology ; Signal Transduction/genetics ; Signal Transduction/physiology ; Substrate Specificity/physiology ; Transcription Factor RelA
Chemical Substances	Chromatin ; Isoenzymes ; NF-kappa B ; Nuclear Proteins ; Transcription Factor RelA ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; CHUK protein, human (EC 2.7.11.10) ; I-kappa B Kinase (EC 2.7.11.10) ; IKBKB protein, human (EC 2.7.11.10) ; IKBKE protein, human (EC 2.7.11.10)
Language	English
Publishing date	2005-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.175.3.1834
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Article ; Online: Constitutive association of TGF-beta-activated kinase 1 with the IkappaB kinase complex in the nucleus and cytoplasm of human neutrophils and its impact on downstream processes.

Ear, Thornin / Fortin, Carl F / Simard, François A / McDonald, Patrick P

Journal of immunology (Baltimore, Md. : 1950)

2010 Volume 184, Issue 7, Page(s) 3897–3906

Abstract: Neutrophils influence innate and adaptative immunity by generating numerous mediators whose regulation largely depends on the IkappaB kinase (IKK)/IkappaB/NF-kappaB signaling cascade. A singular feature of neutrophils is that they express several ... ...

Abstract	Neutrophils influence innate and adaptative immunity by generating numerous mediators whose regulation largely depends on the IkappaB kinase (IKK)/IkappaB/NF-kappaB signaling cascade. A singular feature of neutrophils is that they express several components of this pathway (namely, NF-kappaB/Rel proteins and IkappaB-alpha) in both the nucleus and cytoplasm. We recently reported that the IKK complex of neutrophils is similarly expressed and activated in both cellular compartments. However, the upstream IKK kinase has not yet been identified. In this study, we report that neutrophils express the mitogen-activated protein 3 kinase, TGF-beta-activated kinase 1 (TAK1), as well as its associated partners, TAK1-binding protein (TAB) 1, TAB2, and TAB4, in both the cytoplasm and nucleus. Following cell stimulation by TNF-alpha or LPS, TAK1 becomes rapidly and transiently activated. Blocking TAK1 kinase activity with a highly selective inhibitor (5z-7-oxozeaenol) attenuated the phosphorylation of nuclear and cytoplasmic IKKalpha/beta, IkappaB-alpha, and RelA, and also impaired IkappaB-alpha degradation and NF-kappaB DNA binding in activated neutrophils. Moreover, TAK1 was found to be involved in the activation of p38 MAPK and ERK, which also influence cytokine generation in neutrophils. As a result, inflammatory cytokine expression and release were profoundly impaired following TAK1 inhibition. Similarly, the delayed apoptosis observed in response to LPS or TNF-alpha was reversed by TAK1 inhibition. By contrast, IKKgamma phosphorylation and STAT1 activation were unaffected by TAK1 inhibition. Our data establish the central role of TAK1 in controlling nuclear and cytoplasmic signaling cascades in primary neutrophils, making it a promising target for therapeutic intervention in view of the foremost role of neutrophils in several chronic inflammatory conditions.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Cell Nucleus/enzymology ; Cell Nucleus/immunology ; Cytoplasm/enzymology ; Cytoplasm/immunology ; Electrophoretic Mobility Shift Assay ; Enzyme Activation/immunology ; Enzyme-Linked Immunosorbent Assay ; Humans ; I-kappa B Kinase/immunology ; I-kappa B Kinase/metabolism ; Immunoblotting ; Immunoprecipitation ; MAP Kinase Kinase Kinases/immunology ; MAP Kinase Kinase Kinases/metabolism ; Neutrophils/enzymology ; Neutrophils/immunology ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/immunology ; Transfection
Chemical Substances	Adaptor Proteins, Signal Transducing ; RNA, Messenger ; TAB1 protein, human ; TAB2 protein, human ; TAB4 protein, human ; I-kappa B Kinase (EC 2.7.11.10) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP kinase kinase kinase 7 (EC 2.7.11.25)
Language	English
Publishing date	2010-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.0902958
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Article: Autocrine role of endogenous interleukin-18 on inflammatory cytokine generation by human neutrophils

Fortin, Carl F / Ear, Thornin / McDonald, Patrick P

FASEB journal. 2009 Jan., v. 23, no. 1

2009

Abstract: ... Fortin, C. F., Ear, T., McDonald, P. P. Autocrine role of endogenous interleukin-18 on inflammatory ...

Abstract	Neutrophils are key players of innate immunity and influence inflammatory and immune reactions through the production of numerous cytokines. Interleukin-18 (IL-18) is known to stimulate several neutrophil responses, and recent evidence suggests that neutrophils might represent a source of IL-18. Here, we show that neutrophils constitutively produce both IL-18 and its antagonist, IL-18BP. Cell activation does not affect IL-18BP release but leads to an increased gene expression and secretion of IL-18, a process that depends on NF-κB activation. Moreover, endogenous IL-18 feeds back on the neutrophils to augment cytokine generation in lipopolysaccharide-treated cells. Accordingly, exogenous IL-18 can induce the gene expression and release of several inflammatory cytokines in neutrophils, including its own expression. We finally report that IL-18 activates the p38 MAPK, MEK/ERK, and PI3K/Akt pathways in neutrophils. The IKK cascade is also activated by IL-18, resulting in IκB-α degradation, NF-κB activation, and RelA phosphorylation. Accordingly, these pathways contribute to the generation of inflammatory cytokines in IL-18-stimulated neutrophils. By contrast, the phosphorylation and DNA-binding activity of various STAT proteins were not induced by IL-18. Collectively, our results unveil new interactions between IL-18 and neutrophils and further support a role for these cells in influencing both innate and adaptive immunity.--Fortin, C. F., Ear, T., McDonald, P. P. Autocrine role of endogenous interleukin-18 on inflammatory cytokine generation by human neutrophils.
Language	English
Dates of publication	2009-01
Size	p. 194-203.
Publishing place	The Federation of American Societies for Experimental Biology
Document type	Article
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A class IA PI3K controls inflammatory cytokine production in human neutrophils.

Fortin, Carl F / Cloutier, Alexandre / Ear, Thornin / Sylvain-Prévost, Stéphanie / Mayer, Thomas Z / Bouchelaghem, Rim / McDonald, Patrick P

European journal of immunology

2011 Volume 41, Issue 6, Page(s) 1709–1719

Abstract: Neutrophils are generally the first leukocytes to arrive at sites of inflammation or injury, where they release a variety of inflammatory mediators, which contribute to shaping the ensuing immune response. Here, we show that in neutrophils exposed to ... ...

Abstract	Neutrophils are generally the first leukocytes to arrive at sites of inflammation or injury, where they release a variety of inflammatory mediators, which contribute to shaping the ensuing immune response. Here, we show that in neutrophils exposed to physiological stimuli (i.e. LPS and TNF-α), inhibition of the PI3K signaling pathway impairs the synthesis and secretion of IL-8, Mip-1α, and Mip-1β. Further investigation showed that Mip-1α and Mip-1β gene transcription was similarly decreased, whereas IL-8 transcription and steady-state mRNA levels were unaffected. Accordingly, PI3K inhibition had no impact on NF-κB or C/EBP activation, which are essential for IL-8 transcription, but the basis for this selective inhibition of chemokine transcription remains elusive. We nevertheless identified translational targets of the PI3K pathway (S6, S6 kinase, 4E-BP1). Inhibitor studies and overexpression experiments further established that the various effects of PI3K on chemokine production can be ascribed to p85α and p110δ subunits. Finally, we show that in LPS- and TNF-activated neutrophils, PI3K acts downstream of the kinases p38 MAPK and TAK1. Given the importance of neutrophils and their products in numerous chronic inflammatory disorders, the PI3K pathway could represent an attractive therapeutic target.
MeSH term(s)	Cell Line, Transformed ; Chromones/pharmacology ; Class Ia Phosphatidylinositol 3-Kinase/immunology ; Class Ia Phosphatidylinositol 3-Kinase/metabolism ; Cytokines/metabolism ; Humans ; Imidazoles/pharmacology ; Inflammation Mediators/immunology ; Inflammation Mediators/metabolism ; Lipopolysaccharides/immunology ; Lipopolysaccharides/metabolism ; MAP Kinase Kinase Kinases/antagonists & inhibitors ; Morpholines/pharmacology ; Neutrophil Activation/drug effects ; Neutrophils/drug effects ; Neutrophils/immunology ; Neutrophils/metabolism ; Neutrophils/pathology ; Phosphoinositide-3 Kinase Inhibitors ; Pyridines/pharmacology ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/immunology ; Tumor Necrosis Factor-alpha/metabolism ; Zearalenone/analogs & derivatives ; Zearalenone/pharmacology ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
Chemical Substances	7-oxozeanol ; Chromones ; Cytokines ; Imidazoles ; Inflammation Mediators ; Lipopolysaccharides ; Morpholines ; Phosphoinositide-3 Kinase Inhibitors ; Pyridines ; Tumor Necrosis Factor-alpha ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; Zearalenone (5W827M159J) ; Class Ia Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; MAP Kinase Kinase Kinases (EC 2.7.11.25) ; MAP kinase kinase kinase 7 (EC 2.7.11.25) ; 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole (PVX798P8GI)
Language	English
Publishing date	2011-05-09
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201040945
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