IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C

Fiebich, Bernd L.; Akundi, Ravi Shankar; Biber, Knut; Hamke, Maike; Schmidt, Claudia; Butcher, R.D.; Calker, Dietrich van; Willmroth, Frank

doi:10.1016/j.neuint.2004.11.009

Cited by 39 publications

(35 citation statements)

References 78 publications

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“…These results are in agreement with those obtained in various cell types of different origins, such as pituitary folliculostellate cells (Rees et al, 2003), bronchial smooth muscle cells (Zhong et al, 2004), osteoblasts (Evans et al, 2006), astrocytoma cells (Fiebich et al, 2005), astroglioma cells (Fiebich et al, 1996) and astrocytes (Schwaninger et al, 1997), that all show NECA-induced IL-6 release was via the A2B receptor. Recently, Sergey et al, using A2B adenosine receptor knockout mice, indicated that genetic ablation of A2B receptors abrogated NECA-induced IL-6 release from mouse peritoneal macrophages (Ryzhov et al, 2008).…”

Section: Discussionsupporting

confidence: 92%

“…p38 MAPK has been found to mediate the effects of A 2B receptor stimulation in other cell models. Feoktistov et al (1999) indicated that the p38 MAPK pathway is essential for adenosine A2BR-dependent stimulation of IL-8 production in HMC-1 cells, and Fiebich et al (2005) reported that p38 MAPK is crucial for the NECA-induced signalling cascade that leads to increased IL-6 synthesis in U373 MG cells. We also demonstrated that a PKC-d isoform translocation inhibitor peptide, but not a PKC-e inhibitor peptide, inhibited NECA-stimulated p38 MAPK phosphorylation, which indicates that PKC-d functions as an upstream regulator of p38 MAPK in this process.…”

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confidence: 99%

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Stimulation of adenosine A_2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Wei

Song

Chen

et al. 2010

British J Pharmacology

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Background and purpose: Inflammatory response and cytokine activation are markedly stimulated after myocardial infarction, and contribute to cardiac remodelling. Interleukin-6 (IL-6), a pro-inflammatory cytokine, has pleiotropic effects on cardiac remodelling. Adenosine, released by all cell types, binds to a class of G protein-coupled receptors to induce various cardiovascular effects. The aim of this work was to investigate whether activation of adenosine receptors, particularly A2B adenosine receptors, could stimulate IL-6 secretion in cardiac fibroblasts (CFs). Experimental approach: ELISA was used to assess IL-6 concentration in supernatant, and immunostaining was used to analyse IL-6 protein level in CFs. The levels of phosphorylated and total p38, extracellular signal-regulated kinase, c-Jun N-terminal kinase and protein kinase C-d (PKC-d) were determined by Western blot analysis. Key results: Adenosine-5′-N-ethyluronamide (NECA), a stable adenosine analogue, dose-and time-dependently stimulated IL-6 secretion in CFs. The effect of NECA was dose-dependently inhibited by an A2B antagonist, and silencing of the A2B receptor also inhibited IL-6 secretion. By using PKC isoform-selective inhibitors and translocation peptide inhibitors, the PKC-d isoform was found to be involved in the up-regulation of IL-6 production. Inhibition of p38 by SB203580, and adenoviral transfer of dominant-negative p38 inhibited NECA-induced IL-6 production. Furthermore, PKC-d functioned as an upstream regulator of p38 MAPK in this process. Conclusions and implications:We demonstrated a novel relationship between adenosine and IL-6 secretion, in that IL-6 secretion induced by NECA was mediated by adenosine A2B receptor activation in CFs and was dependent on a PKCd-P38 pathway.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Stimulation of adenosine A_2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Wei

Song

Chen

et al. 2010

British J Pharmacology

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“…The low-affinity A 2B receptor was known to mediate proinflammatory effects of adenosine by up-regulating cytokines and growth factors. This view has been supported by a large body of evidence provided by pharmacological analysis of adenosine-dependent cytokine and growth factor secretion in various cells, tissues, and organs (Feoktistov and Biaggioni, 1995;Fiebich et al, 1996Fiebich et al, , 2005Schwaninger et al, 1997;Feoktistov et al, 2002;Rees et al, 2003;Zeng et al, 2003;Ryzhov et al, 2004;Zhong et al, 2004Zhong et al, , 2005Evans et al, 2006;Sun et al, 2006b). This concept has been recently challenged by findings that A 2B KO mice exhibit moderate inflammation primarily caused by elevated basal and LPSstimulated plasma TNF-␣ (Yang et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

“…A 2B receptors stimulated IL-8 production in human microvascular endothelial (Feoktistov et al, 2002) and glioblastoma (Zeng et al, 2003) cell lines. A 2B receptors were implicated in the stimulation of IL-6 release in osteoblasts (Evans et al, 2006), intestinal epithelial cells (Sitaraman et al, 2001), pituitary folliculostellate cells (Rees et al, 2003), astrocytes (Schwaninger et al, 1997), astrocytoma cells (Fiebich et al, 2005), and astroglioma cells (Fiebich et al, 1996). For this and other reasons, A 2B receptors have been suggested to mediate proinflammatory actions of adenosine.…”

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confidence: 99%

Effect of A_2BAdenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines

Ryzhov

Zaynagetdinov

Goldstein

et al. 2007

J Pharmacol Exp Ther

108

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Pharmacological studies suggest that A 2B adenosine receptors mediate proinflammatory effects of adenosine. This concept was recently challenged by the finding that A 2B adenosine receptor knockout (A 2B KO) mice had moderate inflammation due to elevated basal plasma tumor necrosis factor (TNF)-␣ and an exaggerated response to lipopolysaccharide (LPS) challenge. However, it is unclear whether this phenomenon actually reflects the loss of putative taming of proinflammatory cytokine production via activation of A 2B receptors by endogenous adenosine. In this report, we examined adenosine receptor-dependent regulation of interleukin (IL)-6 and TNF-␣ blood plasma levels in A 2B KO and wild-type mice in vivo and their release from peritoneal macrophages ex vivo. Stimulation of adenosine receptors with 5Ј-N-ethylcarboxamidoadenosine (NECA) up-regulated IL-6 and suppressed LPS-induced TNF-␣ in wild-type mice. The selective A 2B antagonists 3-isobutyl-8-pyrrolidinoxanthine and 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]-1,3-di(npropyl)xanthine (MRS 1754) inhibited NECA-induced IL-6 release but not the suppression of LPS-induced TNF-␣ secretion from macrophages. Genetic ablation of A 2B receptors abrogated NECA-induced increases in IL-6 release from mouse peritoneal macrophages and dramatically reduced the ability of NECA to raise IL-6 plasma levels in vivo. In contrast, the absence of A 2B adenosine receptors did not affect NECA-induced suppression of LPS-activated TNF-␣ release in macrophages, nor did it reduce the ability of NECA to suppress LPS-induced increase in TNF-␣ plasma levels in vivo. Thus, our results indicate that stimulation of A 2B receptors up-regulates the proinflammatory cytokine IL-6 and argue against the recently suggested anti-inflammatory role of A 2B receptors in suppression of LPS-stimulated TNF-␣ production by adenosine.There is growing evidence that adenosine plays an important role in the regulation of inflammation. Adenosine is an intermediate product of adenine nucleotide metabolism, and it also serves as a signaling molecule that can modulate cellular functions via binding to cell surface G-proteincoupled receptors of the P1 purinergic family comprising A 1 , A 2A , A 2B , and A 3 adenosine receptor subtypes. Among adenosine receptors, the A 2B subtype has the lowest affinity to adenosine. Although A 2B receptors are likely to remain silent under normal physiological conditions (Fredholm et al., 2001b), they can be activated during inflammation when interstitial adenosine concentrations are increased as a result of cell stress, injury, and tissue hypoxia (Fredholm et al., 2001a).Many studies suggest that A 2B receptors are involved in adenosine-dependent regulation of proinflammatory paracrine factors. We have shown previously that stimulation of A 2B receptors in human mast cell line HMC-1 increased production of proinflammatory cytokines interleukin (IL)-1␤, IL-3, IL-4, IL-8, and IL-13 (Feoktistov and Biaggioni, 1995;Ryzhov et al., 2004). Studies in human primary cell cultur...

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“…This view has been supported by a large body of evidence provided by pharmacological analysis of adenosinedependent cytokine and growth factor secretion in various cells, tissues, and organs (8,11,13,18,(31)(32)(33)(34)(35)(36)(37)(38). Pharmacological inhibition of A 2B receptors significantly reduced elevations in proinflammatory cytokines as well as mediators of airway remodeling induced by high adenosine levels in the lungs of ADA-deficient mice (8).…”

Section: Discussionmentioning

confidence: 95%

Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells

Ryzhov¹,

Zaynagetdinov²,

Goldstein

et al. 2008

The Journal of Immunology

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We have previously shown that A2B adenosine receptors (AR) play a pro‐inflammatory/pro‐angiogenic role, upregulating production of Th2 cytokines and angiogenic factors in human HMC‐1 mast cells.1,2 However, the pro‐inflammatory role of A2bAR in mast cells was recently questioned by a study that found an enhanced antigen‐induced degranulation of A2bAR knockout (A2BKO) mouse bone marrow‐derived mast cells (BMMCs).3 The authors interpreted this as evidence of anti‐inflammatory actions of A2BAR in BMMCs and suggested that A2BAR antagonists with inverse agonist activity could promote activation of mast cells. Here, we revisited these conclusions by studying the effect of genetic A2BAR ablation on adenosine‐dependent regulation of BMMCs. Our results show that genetic ablation of A2BAR had no effect on adenosine‐dependent potentiation of antigen‐induced degranulation, but abrogated adenosine‐dependent stimulation of IL‐13 and VEGF secretion. A2BAR antagonists with inverse agonist activity inhibited A2BAR‐dependent secretion, but did not mimic the enhanced antigen‐induced degranulation observed in A2BKO BMMCs. Thus, our study confirmed the pro‐inflammatory role of mast cell A2BAR and demonstrated anti‐inflammatory actions of A2BAR antagonists. Supported by NIH.

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IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C

Cited by 39 publications

References 78 publications

Stimulation of adenosine A_2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Stimulation of adenosine A_2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Effect of A_2BAdenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines

Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells

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IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C

Cited by 39 publications

References 78 publications

Stimulation of adenosine A2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Stimulation of adenosine A2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Effect of A2BAdenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines

Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells

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Stimulation of adenosine A_2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Stimulation of adenosine A_2B receptors induces interleukin‐6 secretion in cardiac fibroblasts via the PKC‐δ–P38 signalling pathway

Effect of A_2BAdenosine Receptor Gene Ablation on Adenosine-Dependent Regulation of Proinflammatory Cytokines