Regulation of Eicosanoid Generation in Activated Macrophages

Lim, W.H.; Stewart, Alastair G.

doi:10.1159/000235458

Cited by 5 publications

(5 citation statements)

References 23 publications

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“…Thus, rat peritoneal macrophages express PAF receptors, but these are not cou pled to Os generation, unlike those in the guinea pig. It appears that an increase in [Ca2+]j of the duration of responses induced by PAF is not a sufficient simulus for the gen eration of Os (present findings) or PGF [7] by rat peritoneal macrophages.…”

Section: Discussioncontrasting

confidence: 51%

“…Nevertheless, the se lective, potent and structurally distinct PAF receptor antagonists, CV 6209 [1. 4] or WEB 2086 [5] reduce the basal PGI2 generation in both guinea pig [6] and rat peritoneal macro phages [7] by a mechanism which is clearly distinguishable from direct effects on either phospholipase A2, cyclo-oxygenase or PGI2 synthase [7], The lack of response to exoge nous PAF in rat macrophages is seemingly difficult to reconcile with a specific effect of the PAF receptor antagonists on the basal PGI2 generation.…”

Section: Introductionmentioning

confidence: 99%

“…However, this increase in [Ca2+]j is insuffi cient to elicit the generation of PGIy [7] or Oÿ. Although an increase in [Ca2+]j is neither nec essary nor sufficient for Oÿ generation, it ap pears that a basal level and/or agonist-in duced increase in [Ca2+]j reinforces the signal transduction cascade that initiates or main tains Oÿ generation.…”

mentioning

confidence: 99%

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Importance of Basal and Agonist-Stimulated Intracellular Calcium for Superoxide Anion Generation in Peritoneal Macrophages

Grigoriadis¹,

Lim²,

Stewart³

1993

Cell Physiol Biochem

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The cellular signalling mechanisms initiated by platelet-activating factor (PAF) for stimulation of superoxide anion (O^–₂) generation in peritoneal macrophages were investigated by monitoring intracellular calcium ([Ca²⁺]_i) levels. In rat peritoneal macrophages, exogenous PAF elicited an increase in [Ca²⁺]_i, but there was no O^–₂ generation. PAF elicited similar increases in [Ca²⁺]_i in guinea pig macrophages, which were accompanied by O^-₂ generation. Removal of external calcium revealed that the major component of the PAF-induced increase in [Ca²⁺]_i, in both rat and guina pig peritoneal macrophages, was dependent on transmembrane Ca²⁺ flux. Pertussis toxin pretreatment had no effect on basal or PAF-induced increases in [Ca²⁺]_i. In guinea pig macrophages, removal of external calcium or pertussis toxin pretreatment reduced O^–₂ generation by approximately 50% and the combination of these pretreatments caused almost complete suppression of the response. Thus, additional second mesenger systems are activated in guinea pig macrophages following PAF receptor activation which appear to be essential for O^–₂ generation.

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Section: Discussioncontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

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Importance of Basal and Agonist-Stimulated Intracellular Calcium for Superoxide Anion Generation in Peritoneal Macrophages

Grigoriadis¹,

Lim²,

Stewart³

1993

Cell Physiol Biochem

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“…Prostaglandin E 2 levels were determined in a volume of 100 μL of the unextracted culture medium harvested immediately prior to the addition of [ 3 H]‐thymidine. The radioimmunoassay of PGE 2 was carried out using a commercially available antibody (UBI, Lake Placid, NY, U.S.A.) and methods of Salmon (1978) as described previously ( Lim & Stewart, 1991 ). The limit of detection of the assay was 0.05 n M , and its cross‐reactivities (as determined by the supplier) were as follows: PGE 2 100%, PGE 1 100%, PGF 2α 3%, PGF 1α 2% and TXB 2 0%.…”

Section: Methodsmentioning

confidence: 99%

Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Vlahos

Stewart

1999

British J Pharmacology

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1 Previous studies have established that glucocorticoids inhibit airway smooth muscle DNA synthesis. The eects of a combination of the pro-in¯ammatory cytokines, interleukin-1a (IL-1a) and tumour necrosis factor-a (TNF-a) on the inhibition of DNA synthesis by glucocorticoids in human cultured airway smooth muscle have now been investigated, since these cytokines are chronically expressed in asthmatic airways. 2 Thrombin (0.3 u ml 71 ) and basic ®broblast growth factor (bFGF, 300 pM) stimulated increases in DNA synthesis which were concentration-dependently inhibited by dexamethasone (1 ± 1000 nM). 3 The cytokine mixture, comprising IL-1a (0.01 and 0.1 pM) and TNF-a (3 and 30 pM), directly evoked increases in DNA synthesis which were attenuated by dexamethasone. However, the cytokine mixture prevented responses to bFGF or thrombin. 4 Paradoxically, in the presence of the cytokine mixture and bFGF, dexamethasone (1 ± 1000 nM) concentration-dependently increased DNA synthesis. Furthermore, neither dexamethasone (100 nM) nor¯uticasone propionate (1 nM) inhibited DNA synthesized in response to bFGF/cytokine mixture combination and dexamethasone was similarly inactive against the thrombin/cytokine mixture. 5 The levels of prostaglandin E 2 (PGE 2 ), an established inhibitor of airway smooth muscle DNA synthesis, remained below the limits of assay detection (0.05 nM) under basal conditions or following stimulation with either thrombin or bFGF. In contrast, the cytokine mixture alone, and in the presence of thrombin or bFGF, induced biologically active levels of PGE 2 . Dexamethasone (100 nM), the non-selective cyclo-oxygenase (COX) inhibitor indomethacin (3 mM) or the selective COX-2 inhibitor L-745,337 (0.3 mM) completely inhibited synthesis of PGE 2 . 6 Neither indomethacin (3 mM) nor L-745,337 (0.3 mM) in¯uenced thrombin-or bFGF-induced DNA synthesis. However, each COX inhibitor enhanced DNA synthesis in cytokine-treated cells. 7 In unstimulated airway smooth muscle cells, COX-1, but not COX-2 protein was detectable by Western blotting. The induction of COX-2 protein by the cytokine mixture was attenuated by dexamethasone (100 nM), whereas the level of COX-1 protein was unaected by either the cytokines or by dexamethasone. 8 Cytokine-induced, COX-2-dependent eicosanoid production inhibits DNA synthesis. The paradoxical increase in DNA synthesis observed in glucocorticoid treated airway smooth muscle stimulated by cytokine/bFGF combinations may be explained by the ability of glucocorticoids to repress COX-2 induction and prevent cytokine-induction of the DNA synthesis inhibitor, PGE 2 .

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“…In contrast, in rat perito neal macrophages, PAF did not stimulate the tyrosine phosphorylation of the high molecu lar weight proteins, nor did it elicit the genera tion of 05. Additionally, it appears that an increase in [Ca2+]j of the duration of responses induced by PAF in rat peritoneal macro phages is not a sufficient signal for the genera tion of 05 [8] or PGF [22], The qualitative differences in the PAFstimulated tyrosine phosphorylation between rat and guinea pig macrophages are consistent with an important role for tyrosine kinase(s) in 05 generation. The increased phosphoryla tion of the 145-and 132-kD proteins in guin ea pig macrophages prompted us to investi gate whether a stimulant of 05 generation could also stimulate a similar increase in tyro sine phosphorylation in rat peritoneal macro phages.…”

Section: Discussionmentioning

confidence: 91%

Role of Tyrosine Phosphorylation in the Signalling of Superoxide Anion Generation in Platelet-Activating-Factor-Stimulated Peritoneal Macrophages

Grigoriadis¹,

Stewart²

1996

Cell Physiol Biochem

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The signalling pathway(s) involved in the activation of superoxide anion (O^–₂) generation by platelet-activating factor (PAF) are not well understood, But elevations of sn-l,2-diacylglycerol and intracellular calcium contribute to activation by stimulating protein kinase C activity. Since recent studies have suggested that tyrosine phosphorylation may also be a component of the signalling of O^–₂ generation in human neutrophils, we have investigated whether PAF stimulates tyrosine phosphorylation in guinea pig and rat macrophages. PAF (10 nM) stimulated tyrosine phosphorylation within 10–30 s, coinciding with the onset of the O^-₂ generation in guinea pig peritoneal macrophages. At 30 min after exposure of guinea pig macrophages to PAF, the phosphorylation levels were similar to those of unstimulated cells. In contrast, in rat peritoneal macrophages, PAF did not stimulate tyrosine phosphorylation of high molecular weight proteins, nor did it elicit the generation of O^–₂. PAF-induced O^–₂ generation was inhibited by pre-treatment of guinea pig peritoneal macrophages with the protein tyrosine kinase inhibitors methyl 2, 5-dihydroxymethylcinnamate and tyrphostin. The qualitative difference between PAF-induced phosphorylation patterns in rat and guinea pig macrophages and the inhibitory effects of protein tyrosine kinase inhibition are consistent with an important role for protein tyrosine kinase(s) in O^–₂ generation.

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Regulation of Eicosanoid Generation in Activated Macrophages

Cited by 5 publications

References 23 publications

Importance of Basal and Agonist-Stimulated Intracellular Calcium for Superoxide Anion Generation in Peritoneal Macrophages

Importance of Basal and Agonist-Stimulated Intracellular Calcium for Superoxide Anion Generation in Peritoneal Macrophages

Interleukin‐1α and tumour necrosis factor‐α modulate airway smooth muscle DNA synthesis by induction of cyclo‐oxygenase‐2: inhibition by dexamethasone and fluticasone propionate

Role of Tyrosine Phosphorylation in the Signalling of Superoxide Anion Generation in Platelet-Activating-Factor-Stimulated Peritoneal Macrophages

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