Oxidative Stress Reprograms Lipopolysaccharide Signaling via Src Kinase-dependent Pathway in RAW 264.7 Macrophage Cell Line

Khadaroo, Rachel G.; Kapùs, András; Powers, Kinga A.; Cybulsky, Myron I.; Marshall, John C.; Rotstein, Ori D.

doi:10.1074/jbc.m302660200

Cited by 57 publications

(46 citation statements)

References 31 publications

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“…These results suggest that the balance between stimulatory and inhibitory regulation of Src family kinases is complicated and may make interpretation of DC phenotypes in multikinase-deficient mice difficult. This same argument applies to studies using Src family kinase inhibitors, such as PP1 and PP2, to study the contributions of these enzymes to DC function (15)(16)(17)(18)(19)(20)(22)(23)(24). However, our results support the model that Lyn plays unique roles in DC generation and maturation, and that other Src family kinases cannot compensate for its function.…”

Section: Discussioncontrasting

confidence: 53%

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The Lyn Tyrosine Kinase Differentially Regulates Dendritic Cell Generation and Maturation

Chu

Lowell

2005

The Journal of Immunology

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The Src family kinase Lyn plays both stimulatory and inhibitory roles in hemopoietic cells. In this report we provide evidence that Lyn is involved in dendritic cell (DC) generation and maturation. Loss of Lyn promoted DC expansion in vitro from bone marrow precursors due to enhanced generation and accelerated differentiation of Lyn-deficient DC progenitors. Differentiated Lyn-deficient DCs also had a higher survival rate. Similarly, the CD11c-positive cell number was increased in aged Lyn-deficient mice in vivo. In contrast to their enhanced generation, lyn−/− DCs failed to mature appropriately in response to innate stimuli, resulting in DCs with lower levels of MHC class II and costimulatory molecules. In addition, IL-12 production and Ag-specific T cell activation were reduced in lyn−/− DCs after maturation, resulting in impaired Th1 responses. This is the first study to characterize Lyn-deficient DCs. Our results suggest that Lyn kinase plays uniquely negative and positive regulatory roles in DC generation and maturation, respectively.

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Section: Discussioncontrasting

confidence: 53%

“…Numerous studies have implicated these kinases in LPS signaling, primarily in macrophages (13)(14)(15)(16)(17)(18)(19)(20). In addition, Src family kinases are involved in signaling events in DCs.…”

Section: Endritic Cells (Dcs)mentioning

confidence: 99%

The Lyn Tyrosine Kinase Differentially Regulates Dendritic Cell Generation and Maturation

Chu

Lowell

2005

The Journal of Immunology

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“…Such crosstalk is observed in macrophages that undergo oxidative stress and are then primed to respond to lower doses of LPS, which allows for more robust inflammatory responses under stress conditions. At low doses of LPS, PP2 does not inhibit activation of p38 or NF kappa B, however, pretreatment of macrophages with H 2 O 2 in order to induce oxidative stress causes low dose LPS signaling to become SFK-dependent (135,136). This is also observed in an in vivo model (see section 4.2).…”

Section: Macrophage Innate Immune Functionmentioning

confidence: 51%

The diverse functions of Src family kinases in macrophages

Abram

Lowell²

2008

Front Biosci

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Macrophages are key components of the innate immune response. These cells possess a diverse repertoire of receptors that allow them to respond to a host of external stimuli including cytokines, chemokines, and pathogen-associated molecules. Signals resulting from these stimuli activate a number of macrophage functional responses such as adhesion, migration, phagocytosis, proliferation, survival, cytokine release and production of reactive oxygen and nitrogen species. The cytoplasmic tyrosine kinase Src and its family members (SFKs) have been implicated in many intracellular signaling pathways in macrophages, initiated by a diverse set of receptors ranging from integrins to Toll-like receptors. However, it has been difficult to implicate any given member of the family in any specific pathway. SFKs appear to have overlapping and complementary functions in many pathways. Perhaps the function of these enzymes is to modulate the overall intracellular signaling network in macrophages, rather than operating as exclusive signaling switches for defined pathways. In general, SFKs may function more like rheostats, influencing the amplitude of many pathways. KeywordsTyrosine kinases; signal transduction; innate immunity; integrins; Toll-like receptors; ITIM; ITAM; adhesion; migration; Hck; Fgr; Lyn; Review INTRODUCTION Src family kinases -general approachesc-Src was first described as the cellular counterpart of v-Src, the transforming gene found in Rous Sarcoma Virus, and has since been the focus of much research. Src and its other family members, referred to as Src Family Kinases (SFKs) throughout this review, have been implicated in many diverse signaling pathways in both immune (1) and non-immune cell types (2). This is apparent from the close to 25,000 PubMed hits one gets when researching these enzymes. Furthermore, a strong clinical interest has developed in SFKs based on the growing realization of their central roles in human cancer (3, 4).Src family members include c-Src, Fyn, c-Yes, Lck, Hck, c-Fgr, Lyn, Blk, and Yrk. Src, Fyn and Yes are ubiquitously expressed whereas Lck, Hck, Fgr, Lyn and Blk tend to be more restricted to cells of hematopoietic origin. Yrk has only been found in chickens. The SFKs Send correspondence to: Dr Clifford Lowell, Department of Laboratory Medicine, University of California, San Francisco, S1058, 513 Parnassus Avenue, San Francisco, CA94143-0451, Tel: 415-476-2540, Fax: 415-502-9404, clifford.lowell@ucsf.edu. HHS Public AccessAuthor manuscript Front Biosci. Author manuscript; available in PMC 2015 June 05. Published in final edited form as:Front Biosci. ; 13: 4426-4450. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript are cytoplasmic tyrosine kinases, consisting of an N-terminal unique domain, a Src homology 3 (SH3) domain that can interact with polyproline-rich motifs, a Src homology 2 (SH2) domain that binds phosphotyrosine residues, and a tyrosine kinase domain ( Figure 1A). Acylation of SFKs at their N-terminus (palmitoylation and/or myristoylation) al...

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“…H 2 O 2 -dependent increases in S-glutathionylation of IKKb (53), oxidation of IkB-a at methionine 45 (54), cysteine thiol oxidation of the p50 subunit of NF-kB (55), as well as inhibition of proteasome-dependent degradation of IkB-a result in diminished NF-kB signaling. However, not all of these inhibitory effects of H 2 O 2 have been found in all cell types (56)(57)(58). For example, the ability of H 2 O 2 to reduce LPS-induced proteasomal activity, which was recently described in neutrophils, was not present in macrophages (11).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Respiratory Complex I Regulates Neutrophil Activation and Severity of Lung Injury

Żmijewski

Lorne²,

Zhao³

et al. 2008

Am J Respir Crit Care Med

155

176

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Rationale: Mitochondria have important roles in intracellular energy generation, modulation of apoptosis, and redox-dependent intracellular signaling. Although reactive oxygen species (ROS) participate in the regulation of intracellular signaling pathways, including activation of nuclear factor (NF)-kB, there is only limited information concerning the role of mitochondrially derived ROS in modulating cellular activation and tissue injury associated with acute inflammatory processes. Objectives: To examine involvement of the mitochondrial electron transport chain complex I on LPS-mediated NF-kB activation in neutrophils and neutrophil-dependent acute lung injury. Methods: Neutrophils incubated with rotenone or metformin were treated with bacterial lipopolysaccharide (LPS) to determine the effects of mitochondrial complex I inhibition on intracellular concentrations of reactive oxygen species, NF-kB activation, and proinflammatory cytokine expression. Acute lung injury was produced by intratracheal injection of LPS into control, metformin, or rotenonetreated mice. Measurements and Main Results: Inhibition of complex I with either rotenone or the antihyperglycemic agent metformin was associated with increased intracellular levels of both superoxide and hydrogen peroxide, as well as inhibition of LPS-induced IkB-a degradation, NFkB nuclear accumulation, and proinflammatory cytokine production. Treatment of LPS-exposed mice with rotenone or metformin resulted in inhibition of complex I in the lungs, as well as diminished severity of lung injury.Conclusions: These results demonstrate that mitochondrial complex I plays an important role in modulating Toll-like receptor 4-mediated neutrophil activation and suggest that metformin, as well as other agents that inhibit mitochondrial complex I, may be useful in the prevention or treatment of acute inflammatory processes in which activated neutrophils play a major role, such as acute lung injury.

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Oxidative Stress Reprograms Lipopolysaccharide Signaling via Src Kinase-dependent Pathway in RAW 264.7 Macrophage Cell Line

Cited by 57 publications

References 31 publications

The Lyn Tyrosine Kinase Differentially Regulates Dendritic Cell Generation and Maturation

The Lyn Tyrosine Kinase Differentially Regulates Dendritic Cell Generation and Maturation

The diverse functions of Src family kinases in macrophages

Mitochondrial Respiratory Complex I Regulates Neutrophil Activation and Severity of Lung Injury

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