Regulation of Monokine Gene Expression: Prostaglandin E2 Suppresses Tumor Necrosis Factor but Not Interleukin-1α or β-mRNA and Cell-Associated Bioactivity

Scales, W. E.; Chensue, Stephen W.; Otterness, Ivan G.; Kunkel, S. L.

doi:10.1002/jlb.45.5.416

Cited by 131 publications

(59 citation statements)

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“…This finding was unexpected based on previous evidence that both IL-6 and TNF-a are typically regulated by the same transcription factor, NF-kB. 35 While not tested here, AngII has been shown to promote prostaglandin production, in particular prostaglandin E2 (PGE2), which in turn has been shown to inhibit the production of TNF-a while enhancing IL-6 production, thus supporting our findings 36,37 The pro-inflammatory nature of IL-6 is supported by evidence that the expression of IL-1, a well-known pro-inflammatory cytokine, was also upregulated by AngII exposure. 38 In summary, we provide evidence that there is variable expression of AT 1 R in subsets of purified monocytes, with greater expression seen in CD14 + /CD16 + monocytes.…”

Section: Mediasupporting

confidence: 80%

Highly purified human peripheral blood monocytes produce IL-6 but not TNFα in response to angiotensin II

Gelinas

Falkenham

Oxner

et al. 2011

J Renin Angiotensin Aldosterone Syst

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Hypothesis: Monocytes produce pro-inflammatory cytokines in response to Angiotensin II (AngII). Introduction: AngII has been suggested by many to be pro-inflammatory and likely to contribute to the migration of leukocytes in patients with cardiovascular conditions. Materials and methods: Monocytes were purified from peripheral blood mononuclear cells (PBMCs) by negative selection using antibodies conjugated to magnetic beads. Detection of CD14 + and AT 1 R expression was achieved by double-labeling flow cytometry. Highly purified monocytes were then stimulated with AngII (6 and 24 h) to assess IL-6 and TNF-a transcript levels by qRT-PCR and protein secretion by ELISA. Results: Monocytes comprised 9.7 ± 2.0% of the PBMCs. Monocyte isolation by negative selection yielded a purity of up to 99.8%. We demonstrated AT 1 R expression on 9.5 ± 0.3% of highly purifed CD14 + /CD16 -monocytes. Stimulation of highly purified monocytes with AngII resulted in increased transcript levels of IL-6 at 6 h but not at 24 h, and increased secretion of IL-6 in a dose-dependent manner compared with controls (p <0.01). Conversely, there was no increase in TNF-a mRNA transcripts or protein secretion. Conclusions: We provide evidence that a CD14 + /CD16 -subset of highly purified human monocytes express AT 1 R and respond to AngII exposure in vitro by producing IL-6 but not TNF-a.

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Section: Mediasupporting

confidence: 80%

Highly purified human peripheral blood monocytes produce IL-6 but not TNFα in response to angiotensin II

Gelinas

Falkenham

Oxner

et al. 2011

J Renin Angiotensin Aldosterone Syst

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“…For example, PGE 2 inhibits expression of MHC class II proteins (8) and thus may interfere with antigen-presenting functions of the macrophage. Cytokine production is likewise inhibited by PGE 2 (6,7). Our studies have demonstrated that the actions of PGE 2 to suppress cytokine production by macrophages are mediated almost exclusively by the EP4 receptor; PGE 2 has no effect on LPS-stimulated cytokine release in EP4-deficient macrophages.…”

Section: Figurementioning

confidence: 56%

Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse

Nataraj¹,

Thomas²,

Tilley³

et al. 2001

J. Clin. Invest.

258

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“…9). PG-mediated regulation of myeloid TNF production was reported (63,64). We presented only TNF-a release, but other inflammatory mediators might be modulated.…”

Section: Discussionmentioning

confidence: 89%

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

Park

Lee

Kim

et al. 2012

The Journal of Immunology

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Emerging evidence has established that astrocytes, once considered passive supporting cells that maintained extracellular ion levels and served as a component of the blood–brain barrier, play active regulatory roles during neurogenesis and in brain pathology. In the current study, we demonstrated that astrocytes sense H2O2 by rapidly phosphorylating the transcription factor STAT6, a response not observed in microglia. STAT6 phosphorylation was induced by generators of other reactive oxygen species (ROS) and reactive nitrogen species, as well as in the reoxygenation phase of hypoxia/reoxygenation, during which ROS are generated. Src–JAK pathways mediated STAT6 phosphorylation upstream. Experiments using lipid raft disruptors and analyses of detergent-fractionated cells demonstrated that H2O2-induced STAT6 phosphorylation occurred in lipid rafts. Under experimental conditions in which H2O2 did not affect astrocyte viability, H2O2-induced STAT6 phosphorylation resulted in STAT6-dependent cyclooxygenase-2 expression and subsequent release of PGE2 and prostacyclin, an effect also observed in hypoxia/reoxygenation. Finally, PGs released from H2O2-stimulated astrocytes inhibited microglial TNF-α expression. Accordingly, our results indicate that ROS-induced STAT6 phosphorylation in astrocytes can modulate the functions of neighboring cells, including microglia, through cyclooxygenase-2 induction and subsequent release of PGs. Differences in the sensitivity of STAT6 in astrocytes (highly sensitive) and microglia (insensitive) to phosphorylation following brief exposure to H2O2 suggest that astrocytes can act as sentinels for certain stimuli, including H2O2 and ROS, refining the canonical notion that microglia are the first line of defense against external stimuli.

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Regulation of Monokine Gene Expression: Prostaglandin E2 Suppresses Tumor Necrosis Factor but Not Interleukin-1α or β-mRNA and Cell-Associated Bioactivity

Cited by 131 publications

References 0 publications

Highly purified human peripheral blood monocytes produce IL-6 but not TNFα in response to angiotensin II

Highly purified human peripheral blood monocytes produce IL-6 but not TNFα in response to angiotensin II

Receptors for prostaglandin E2 that regulate cellular immune responses in the mouse

Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release

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