Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro

Onozawa, Yoshiko; Fujita, Yoshifumi; Kuwabara, Harumi; Nagasaki, Masaru; Komai, Toru; Oda, Tomiichiro

doi:10.1016/j.ejphar.2012.03.007

Cited by 71 publications

(61 citation statements)

References 27 publications

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“…28 Another report provides an anti-inflammatory role for GPR65 in arthritis. 29 Type II collagen-induced arthritis was increased in GPR65-null mice in comparison to wild-type mice. These studies taken together suggest GPR65 serves as a negative regulator in inflammation.…”

Section: Gpr65 (Tdag8)mentioning

confidence: 99%

“…32 The GPR65 agonist, BTB09089, showed in vitro effects in GPR65 activation of immune cells to inhibit inflammatory response; however, the activity of BTB09089 was not strong enough for the use in animal models in vivo. 29 The GPR68 agonist, lsx, exhibited pro-neurogenic activity and induced hippocampal neurogenesis in young mice. 107 It was also demonstrated that lsx suppressed the proliferation of malignant astrocytes.…”

Section: Development Of Small Molecule Modulators Of the Ph-sensing Gmentioning

confidence: 99%

“…There have been recent developments in the characterization of GPR4 antagonists along with agonists for GPR65 and GPR68. 29,32,50,106 The GPR4 antagonist demonstrated effectiveness in vitro to reduce the GPR4-mediated inflammatory response to acidosis in endothelial cells. 32 The GPR65 agonist, BTB09089, showed in vitro effects in GPR65 activation of immune cells to inhibit inflammatory response; however, the activity of BTB09089 was not strong enough for the use in animal models in vivo.…”

Section: Development Of Small Molecule Modulators Of the Ph-sensing Gmentioning

confidence: 99%

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Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

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Protons (hydrogen ions) are the simplest form of ions universally produced by cellular metabolism including aerobic respiration and glycolysis. Export of protons out of cells by a number of acid transporters is essential to maintain a stable intracellular pH that is critical for normal cell function. Acid products in the tissue interstitium are removed by blood perfusion and excreted from the body through the respiratory and renal systems. However, the pH homeostasis in tissues is frequently disrupted in many pathophysiologic conditions such as in ischemic tissues and tumors where protons are overproduced and blood perfusion is compromised. Consequently, accumulation of protons causes acidosis in the affected tissue. Although acidosis has profound effects on cell function and disease progression, little is known about the molecular mechanisms by which cells sense and respond to acidotic stress. Recently a family of pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), has been identified and characterized. These GPCRs can be activated by extracellular acidic pH through the protonation of histidine residues of the receptors. Upon activation by acidosis the pH-sensing GPCRs can transduce several downstream G protein pathways such as the G s , G q/11 , and G 12/13 pathways to regulate cell behavior. Studies have revealed the biological roles of the pH-sensing GPCRs in the immune, cardiovascular, respiratory, renal, skeletal, endocrine, and nervous systems, as well as the involvement of these receptors in a variety of pathological conditions such as cancer, inflammation, pain, and cardiovascular disease. As GPCRs are important drug targets, small molecule modulators of the pH-sensing GPCRs are being developed and evaluated for potential therapeutic applications in disease treatment.

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Section: Gpr65 (Tdag8)mentioning

confidence: 99%

Section: Development Of Small Molecule Modulators Of the Ph-sensing Gmentioning

confidence: 99%

Section: Development Of Small Molecule Modulators Of the Ph-sensing Gmentioning

confidence: 99%

See 1 more Smart Citation

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

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show abstract

“…This family of receptors is important for pH sensing in normal physiology of the cardiovascular, renal, respiratory, skeletal, immune, endocrine, and nervous systems [3,16,17,20,[24][25][26][27][28][29][30][31][32][33][34][35]. Cells genetically engineered to overexpress the proton-sensing GPCRs have been creatively utilized as a synthetic pH sensor to regulate gene expression in cell culture, bioreactors, and mice in response to pH and CO 2 changes [36].…”

Section: Introductionmentioning

confidence: 99%

GPR4 decreases B16F10 melanoma cell spreading and regulates focal adhesion dynamics through the G13/Rho signaling pathway

Justus

Yang

2015

Experimental Cell Research

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“…Also GPR4 deficient mice have been generated and described to suffer from a form of renal acidosis [19]. GPR4 and TDAG8 have been linked to the regulation of inflammatory cytokines and factors and chemotactic migration of inflammatory cells [20,21,22,23,24,25]. Therefore, we were interested to test if GPR4 modulates glucose homeostasis and if this effect would be associated with changes in the profile of pro-and anti-inflammatory factors in insulin target organs.…”

Section: Introductionmentioning

confidence: 99%

The Proton-Activated Receptor GPR4 Modulates Glucose Homeostasis by Increasing Insulin Sensitivity

Giudici

Velić

Daryadel

et al. 2013

Cell Physiol Biochem

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Background: The proton-activated G protein-coupled receptor GPR4 is expressed in many tissues including white adipose tissue. GPR4 is activated by extracellular protons in the physiological pH range (i.e. pH 7.7 - 6.8) and is coupled to the production of cAMP. Methods: We examined mice lacking GPR4 and examined glucose tolerance and insulin sensitivity in young and aged mice as well as in mice fed with a high fat diet. Expression profiles of pro- and anti-inflammatory cytokines in white adipose tissue, liver and skeletal muscle was assessed. Results: Here we show that mice lacking GPR4 have an improved intraperitoneal glucose tolerance test and increased insulin sensitivity. Insulin levels were comparable but leptin levels were increased in GPR4 KO mice. Gpr4^-/- showed altered expression of PPARα, IL-6, IL-10, TNFα, and TGF-1β in skeletal muscle, white adipose tissue, and liver. High fat diet abolished the differences in glucose tolerance and insulin sensitivity between Gpr4^+/+ and Gpr4^-/- mice. In contrast, in aged mice (12 months old), the positive effect of GPR4 deficiency on glucose tolerance and insulin sensitivity was maintained. Liver and adipose tissue showed no major differences in the mRNA expression of pro- and anti-inflammatory factors between aged mice of both genotypes. Conclusion: Thus, GPR4 deficiency improves glucose tolerance and insulin sensitivity. The effect may involve an altered balance between pro- and anti-inflammatory factors in insulin target tissues.

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Activation of T cell death-associated gene 8 regulates the cytokine production of T cells and macrophages in vitro

Cited by 71 publications

References 27 publications

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

GPR4 decreases B16F10 melanoma cell spreading and regulates focal adhesion dynamics through the G13/Rho signaling pathway

The Proton-Activated Receptor GPR4 Modulates Glucose Homeostasis by Increasing Insulin Sensitivity

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