ArticleCritical care (London, England)2008
Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock.
Article in Critical care (London, England), 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 28 citations in OpenAlex.
- Adrenergic receptors: a key determinant of outcomes in bacterial pneumonia and bacterial sepsis-associated acute lung injury/acute respiratory distress syndrome through participation in pulmonary innate immune response.Frontiers in immunology · 2026Review
- GLP1 receptor agonism alters growth and therapeutic response in prostate cancer.Endocrine-related cancer · 2025Article
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- The Effect of βFrontiers in immunology · 2020Article
- Proinflammatory switch from Gαs to Gαi signaling by Glucagon-like peptide-1 receptor in murine splenic monocyte following burn injury.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2018Article
- Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis.Nature communications · 2017Article
- β-Adrenergic receptor agonist, compound 49b, inhibits TLR4 signaling pathway in diabetic retina.Immunology and cell biology · 2016Article
- Article
- The Effects of Isoproterenol and Propranolol on Cytokine Profile Secretion by Cultured Tumor-infiltrating Lymphocytes Derived from Colorectal Cancer Patients.Cell journal · 2012Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionStimulation of beta2-adrenergic receptors (beta2-ARs) inhibits tumor necrosis factor-alpha (TNF-alpha) release in monocytes. In septic shock, endogenous catecholamines induce beta2-AR downregulation, leading to an increased TNF-alpha release. The aims of this study were to analyze the molecular mechanisms of beta-adrenergic downregulation and to explore therapeutic interventions with maintained anti-inflammatory efficacy in septic shock using the inhibition of phosphodiesterase 4 (PDE4).
methodsWe conducted in vitro stimulation of peripheral blood mononuclear cells of healthy volunteers (n = 20) and patients with septic shock (n = 20) with lipopolysaccharide (LPS) or Staphylococcus aureus enterotoxin B (SEB) without or with isoprenaline, forskolin (an activator of adenylate cyclase), or ropipram (an inhibitor of PDE4). We also conducted flow cytometric analysis of Toll-like receptor (TLR) 4 and TLR2 surface expression and intracellular TNF-alpha production of untreated and stimulated CD14+ monocytes. Protein expression of beta-ARs, of G proteins, of adenylate cyclase, and of TLRs was measured by Western blotting.
resultsInvestigations were done by LPS (100 ng/mL) or SEB (10 ng/mL) when TLR4 and TLR2 were maximally expressed. LPS- or SEB-treated CD14+ monocytes of healthy volunteers were able to produce TNF-alpha. This effect was attenuated by isoprenaline, forskolin, or rolipram in a concentration-dependent manner. In CD14+ monocytes of patients with septic shock, the anti-inflammatory effect of isoprenaline was completely blunted whereas efficacy of forskolin and rolipram was maintained. CD14+ monocytes of healthy volunteers were compared with patients with septic shock: protein expression of beta2-ARs was reduced and inhibitory G protein was increased, whereas no changes in adenylate cyclase and stimulatory G protein were found.
conclusionsIn septic shock, the anti-inflammatory effects of catecholamines are blunted by downregulation of beta2-ARs and upregulation of the inhibitory G protein in CD14+ monocytes. Beta-adrenergic downregulation is overcome by inhibitors of PDE4. These results provide a mechanistic rationale for the therapeutic use of selective PDE4 inhibitors in the treatment of septic shock.
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