THE SRC FAMILY-SELECTIVE TYROSINE KINASE INHIBITOR PP1 BLOCKS LPS AND IFN-α-MEDIATED TNF AND iNOS PRODUCTION IN MURINE MACROPHAGES

Orlicek, Shari L.; Hanke, J H; English, B. Keith

doi:10.1097/00024382-199911000-00004

Cited by 56 publications

(58 citation statements)

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“…The src-family selective tyrosine kinase inhibitor PP1 blocked TNF production by RAW 264.7 murine macrophages stimulated with cell-permeable ceramide analogs Previous work done in our laboratory has shown that PP1 blocks LPS-mediated TNF production in RAW 264.7 cells [13]. In this study, we found that PP1 also potently inhibited TNF secretion by RAW 264.7 cells stimulated with either ceramide analog (Fig.…”

Section: Murine Macrophagessupporting

confidence: 65%

“…At the concentrations tested, PP1 has no effect on the activity of tyrosine kinases of the JAK or ZAP-70/syk families [19]. We have recently reported that PP1 blocked iNOS production in RAW 264.7 cells stimulated with a combination of LPS and rIFN-␥ [13].…”

Section: Murine Macrophagesmentioning

confidence: 84%

“…We and others have previously reported that tyrosine kinase pathways are required for macrophage activation and inflammatory mediator production in response to LPS [11][12][13][14]. The present studies were designed to investigate the potential role of tyrosine phosphorylation pathways in ceramide-mediated macrophage activation.…”

Section: Introductionmentioning

confidence: 98%

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Ceramide-mediated stimulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in murine macrophages requires tyrosine kinase activity

Knapp

English

2000

Journal of Leukocyte Biology

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In macrophages, bacterial lipopolysaccharide (LPS) has been noted to mimic certain effects of the sphingolipid ceramide, suggesting that ceramide may be involved in macrophage activation by LPS and/or that LPS utilizes ceramiderelated signaling pathways. Putative downstream targets of ceramide include a ceramide-activated (serine/threonine) protein kinase (CAPK) and phosphatase (CAPP). However, the potential role of tyrosine phosphorylation pathways in macrophage response to ceramide has not been examined. Herein we report that cell-permeable analogs of ceramide up-regulate both inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) production in RAW 264.7 murine macrophages. Herbimycin A and genistein, potent natural inhibitors of protein tyrosine (but not serine/threonine) phosphorylation, block ceramide-induced iNOS and TNF production. Furthermore, the highly srcfamily selective pyrazolopyrimidine inhibitor PP1 also blocks ceramide-induced iNOS and TNF production in RAW 264.7 cells. We found that PP1 also inhibits ceramide-mediated tyrosine phosphorylation of the src-family kinase hck. These data indicate that src-related tyrosine kinases play a critical role in macrophage activation by ceramide.

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Section: Murine Macrophagessupporting

confidence: 65%

Section: Murine Macrophagesmentioning

confidence: 84%

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Ceramide-mediated stimulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in murine macrophages requires tyrosine kinase activity

Knapp

English

2000

Journal of Leukocyte Biology

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“…LPS has been shown to increase tyrosine phosphorylation in macrophages, and a role for the Src family of non-receptor tyrosine kinases has been implied from work using the inhibitor PP1 (30). As a key downstream target for Src kinases, Btk is an important kinase regulating receptor-dependent signaling in a variety of hematopoietic cell lineages (31).…”

Section: Discussionmentioning

confidence: 99%

Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor κB Activation by Toll-like Receptor 4

Jefferies

Doyle

Brunner

et al. 2003

Journal of Biological Chemistry

267

249

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The Tec family of protein tyrosine kinases, of which Bruton's tyrosine kinase (Btk) 1 is a prototypical member, is involved in a vast array of signaling pathways in cells of hematopoietic lineage. Btk is expressed in all hematopoietic cells except T lymphocytes and natural killer cells. It is critically important for B-cell development as well as mature B-cell activation and survival. It has also been shown to be important for IgEmediated activation of mast cells resulting in allergic reactions. Btk kinase activity and tyrosine phosphorylation have both been shown to increase upon cross-linking or stimulation of the B-cell receptor, the IgE receptor (Fc⑀RII), and a number of cytokine receptors such as those for IL-3, IL-5, IL-6, and IL-10, suggesting a general role for Btk in immune regulation (1-4). Whereas the molecular mechanisms by which the B-cell receptor regulates B-cell proliferation and survival are not well understood, Btk has recently been shown to lie downstream of the B-cell receptor on the pathway regulating activation of the key pro-inflammatory transcription factor NF B (5-8). The biological importance of the signaling function has been shown by naturally occurring loss of function mutations in Btk in human X-linked agammaglobulinemia and its murine counterpart, X-linked immunodeficiency (Xid). These diseases are characterized by a block in B-cell development and defects in B-cell signaling, and in X-linked agammaglobulinemia patients, mutations in Btk are associated associated with an increased frequency of bacterial infections in all organs (9). Studies in Xid mice have also shown reduced responses to LPS stimulation, with nitric oxide (NO) production decreased, and macrophage effector functions impaired (10 -12). This, coupled with the observation that responses to T-independent antigens are impaired in Xid mice, suggests a role for Btk in innate immune responses.Toll-like receptors (TLRs) have an essential function in both innate and adaptive immunity and have evolved to recognize, with high specificity, diverse microbial pathogens (13). TLR4, as the receptor for the Gram-negative bacterial product LPS, is the prototypical member of the family (numbered TLR1-10 in humans) of type I transmembrane receptors, which are characterized by an extracellular leucine-rich repeat domain and an intracellular Toll/IL-1 receptor (TIR) domain, responsible for signaling. Ligands for other family members (except TLR10) have been identified and include bacterial flagellin and unmethylated bacterial CpG motifs for TLR5 and TLR9, respectively; double-stranded RNA for TLR3; and the antiviral compound R-848 recognizing TLR7 and TLR8. Research into how these receptors signal has identified MyD88 and IL-1-receptorassociated kinases (IRAKs) as key proximal signaling components regulating activation of the pro-inflammatory transcription factor NF B in response to LPS (reviewed in Ref. 14). Important differences in the proteins recruited to the different TLR members have also been described. Both TLR2 (the receptor for...

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“…In mast cells, Lyn phosphorylates the membrane protein Cbp, leading to signal inhibition and reduction in degranulation (12). Alternatively, positive regulation occurs when Lyn phosphorylates ITAMs on membrane proteins such as Iga/b and CD19, which recruit proteins such as Syk and phospholipase Cg2 that amplify signaling (11,(13)(14)(15) (23)(24)(25)(26), and studies using pan-SFK inhibitors have implicated SFKs in LPS-induced responses in DCs (24,27) and Mfs (28)(29)(30). We and others have shown that Lyn 2/2 bone marrow-derived DCs (BMDCs) are impaired with respect to LPS-induced maturation and IL-12 secretion, suggesting a positive regulatory role for Lyn in LPS-induced DC activation (31,32).…”

mentioning

confidence: 99%

Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells

Krebs

Chehal

Sio

et al. 2012

The Journal of Immunology

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The innate immune response is a first line of defense against invading pathogens; however, the magnitude of this response must be tightly regulated, as hyper- or suboptimal responses can be detrimental to the host. Systemic inflammation resulting from bacterial infection can lead to sepsis, which remains a serious problem with high mortality rates. Lyn tyrosine kinase plays a key role in adaptive immunity, although its role in innate immunity remains unclear. In this study, we show that Lyn gain-of-function (Lynup/up) mice display enhanced sensitivity to endotoxin and succumb to upregulated proinflammatory cytokine production at a dose well tolerated by control animals. Endotoxin sensitivity in Lynup/up mice depends on dendritic cells (DCs) and NK cells and occurs though a mechanism involving increased maturation and activation of the DC compartment, leading to elevated production of IFN-γ by NK cells. We further show that modulation of endotoxin-induced signal transduction in DCs by Lyn involves the phosphatases Src homology 2 domain-containing phosphatase-1 and SHIP-1. Collectively, we demonstrate that Lyn regulates DC physiology such that alterations in Lyn-dependent signaling have profound effects on the nature and magnitude of inflammatory responses. Our studies highlight how perturbations in signaling pathways controlling DC/NK cell-regulated responses to microbial products can profoundly affect the magnitude of innate immune responses.

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THE SRC FAMILY-SELECTIVE TYROSINE KINASE INHIBITOR PP1 BLOCKS LPS AND IFN-α-MEDIATED TNF AND iNOS PRODUCTION IN MURINE MACROPHAGES

Cited by 56 publications

References 0 publications

Ceramide-mediated stimulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in murine macrophages requires tyrosine kinase activity

Ceramide-mediated stimulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF) accumulation in murine macrophages requires tyrosine kinase activity

Bruton's Tyrosine Kinase Is a Toll/Interleukin-1 Receptor Domain-binding Protein That Participates in Nuclear Factor κB Activation by Toll-like Receptor 4

Lyn-Dependent Signaling Regulates the Innate Immune Response by Controlling Dendritic Cell Activation of NK Cells

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