Adjuvant Arthritis Induces Down-Regulation of G Protein-Coupled Receptor Kinases in the Immune System

Lombardi, Maria Stella; Kavelaars, Annemieke; Cobelens, Pieter M.; Schmidt, Reinhold; Schedlowski, Manfred; Heijnen, Cobi J.

doi:10.4049/jimmunol.166.3.1635

Cited by 113 publications

(77 citation statements)

References 47 publications

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“…Interestingly, the level of expression of GRK2, 3, and 6 in leukocytes is known to be tightly regulated (10). For example, we have shown that in patients with rheumatoid arthritis or in rats after development of adjuvant arthritis or experimental autoimmune encephalomyelitis, the level of GRK2, 3, and 6 is reduced by 50 -80% in leukocytes from the blood or spleen (11)(12)(13). In addition, there is evidence that cytokines as well as oxygen radicals can regulate the level of expression of GRK in leukocytes and other cell types (11,14,15).…”

Section: P Olymorphonuclear Neutrophils (Pmn)mentioning

confidence: 98%

Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Kavelaars

Vroon

Raatgever

et al. 2003

The Journal of Immunology

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Directed migration of polymorphonuclear neutrophils (PMN) is required for adequate host defense against invading organisms and leukotriene B4 (LTB4) is one of the most potent PMN chemoattractants. LTB4 exerts its action via binding to BLT1, a G protein-coupled receptor. G protein-coupled receptors are phosphorylated by G protein-coupled receptor kinases (GRK) in an agonist-dependent manner, resulting in receptor desensitization. Recently, it has been shown that the human BLT1 is a substrate for GRK6. To investigate the physiological importance of GRK6 for inflammation and LTB4 signaling in PMN, we used GRK6-deficient mice. The acute inflammatory response (ear swelling and influx of PMN into the ear) after topical application of arachidonic acid was significantly increased in GRK6−/− mice. In vitro, GRK6−/− PMN showed increased chemokinetic and chemotactic responses to LTB4. GRK6−/− PMN respond to LTB4 with a prolonged increase in intracellular calcium and prolonged actin polymerization, suggesting impaired LTB4 receptor desensitization in the absence of GRK6. However, pre-exposure to LTB4 renders both GRK6−/− as well as wild-type PMN refractory to restimulation with LTB4, indicating that the presence of GRK6 is not required for this process to occur. In conclusion, GRK6 deficiency leads to prolonged BLT1 signaling and increased neutrophil migration.

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Section: P Olymorphonuclear Neutrophils (Pmn)mentioning

confidence: 98%

Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Kavelaars

Vroon

Raatgever

et al. 2003

The Journal of Immunology

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“…Elucidating the mechanisms by which the ␤-arrestin-GRK system participates in chemotactic signaling should enhance understanding of the molecular basis for this extraordinarily important and complex cellular process. It also may shed light on the pathophysiology of certain inf lammatory conditions such as rheumatoid arthritis in which lymphocyte GRK6 is dramatically down regulated (38,39).…”

Section: Discussionmentioning

confidence: 99%

Defective lymphocyte chemotaxis in β-arrestin2- and GRK6-deficient mice

Fong

Premont

Richardson

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

281

233

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Lymphocyte chemotaxis is a complex process by which cells move within tissues and across barriers such as vascular endothelium and is usually stimulated by chemokines such as stromal cell-derived factor-1 (CXCL12) acting via G protein-coupled receptors. Because members of this receptor family are regulated (''desensitized'') by G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and ␤-arrestin binding, we examined signaling and chemotactic responses in splenocytes derived from knockout mice deficient in various ␤-arrestins and GRKs, with the expectation that these responses might be enhanced. Knockouts of ␤-arrestin2, GRK5, and GRK6 were examined because all three proteins are expressed at high levels in purified mouse CD3؉ T and B220؉ B splenocytes. CXCL12 stimulation of membrane GTPase activity was unaffected in splenocytes derived from GRK5-deficient mice but was increased in splenocytes from the ␤-arrestin2-and GRK6-deficient animals. Surprisingly, however, both T and B cells from ␤-arrestin2-deficient animals and T cells from GRK6-deficient animals were strikingly impaired in their ability to respond to CXCL12 both in transwell migration assays and in transendothelial migration assays. Chemotactic responses of lymphocytes from GRK5-deficient mice were unaffected. Thus, these results indicate that ␤-arrestin2 and GRK6 actually play positive regulatory roles in mediating the chemotactic responses of T and B lymphocytes to CXCL12.L eukocytes migrate to sites of inflammation by recognizing a gradient of chemoattractants, and moving toward the chemoattractant source. This process of ligand recognition, cell polarization and directed cell migration is complex, given that a cell needs to integrate numerous signals arising from different spatial orientations to decide in which direction to move. In lymphocytes, the signals that guide the cell in making these decisions arise from chemokine activation of heptahelical G protein-coupled receptors (GPCR) linked to G␣i proteins. Directional migration, however, requires the activity of G␤␥, but not G␣, proteins (1, 2). In addition, Rho family guanosine triphosphatases (GTPases), the phosphoinositide 3-kinases, and possibly extracellular receptor kinases each play important roles in generating the cell polarity and cytoskeletal reorganization required for directional migration (3-7).Migration to chemokine gradients is dose dependent. Chemotaxis occurs at relatively low concentrations of chemokines, but at higher chemokine concentrations, cells become paralyzed and no longer migrate toward the chemoattractant source. The mechanisms by which cells are paralyzed at high chemokine concentrations are not clear but may involve agonist-dependent desensitization and receptor endocytosis mediated by G proteincoupled receptor kinases (GRKs) and arrestins. GRKs phosphorylate serine and threonine residues in the C terminus and intracellular loops of GPCRs, allowing for the association of arrestins that act to prevent heterotrimeric G␣␤␥ protein association with a...

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“…These proteins act as GTPase activating proteins for Gα subunits and can also function as effector antagonists of specific Gα subunits, thereby attenuating signaling through GPCRs such as chemokine receptors. In addition, physiologic modulators of G protein signaling, such as RGS and G protein receptor kinases (75,76), represent potential new therapeutic targets in the treatment of atopy and other inflammatory conditions. Thus, the particular spectrum of GPCR proteins and their expression levels within a cell will determine the duration and magnitude of G protein signaling initiated by chemokines for immunomodulating drug targets.…”

Section: Emerging New Drug Targets For Immune-related Herbal Drug Devmentioning

confidence: 99%

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

Huang¹,

Lin

Liao

et al. 2008

Cell Mol Immunol

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In recent years, studies on evaluation of the therapeutic and toxic activity of herbal medicinal products became available and popular. The advances in modern biotechnology have led to discovery of many new active constituents. However, it is a constant challenge to establish the pharmacological basis for efficacy and safety of herbal medicinal products. A better understanding of the effects and bioavailability of phytopharmaceuticals can help in discovering suitable and rational therapies. In this review, we present the bioavailability studies in immune system that has been conducted for some of the more important or widely used phytopharmaceuticals. Furthermore, various new drug targets worthy of using for drug development in immunomodulating herbal medicine area and their regulatory mechanisms are also discussed. Adverse effects, drug interactions, and contraindications are also discussed which show that caution should be exercised when combining phytopharmaceuticals with chemically derived pharmaceutical components. Cellular & Molecular Immunology. 2008;5(1):23-31.

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Adjuvant Arthritis Induces Down-Regulation of G Protein-Coupled Receptor Kinases in the Immune System

Cited by 113 publications

References 47 publications

Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Defective lymphocyte chemotaxis in β-arrestin2- and GRK6-deficient mice

The Immunopharmaceutical Effects and Mechanisms of Herb Medicine

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