{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T22:21:09Z","timestamp":1791066069363,"version":"4.1.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2008,12,17]],"date-time":"2008-12-17T00:00:00Z","timestamp":1229472000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2008,12,17]],"date-time":"2008-12-17T00:00:00Z","timestamp":1229472000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Crit Care"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Stimulation of beta<jats:sub>2<\/jats:sub>-adrenergic receptors (\u03b2<jats:sub>2<\/jats:sub>-ARs) inhibits tumor necrosis factor-alpha (TNF-\u03b1) release in monocytes. In septic shock, endogenous catecholamines induce \u03b2<jats:sub>2<\/jats:sub>-AR downregulation, leading to an increased TNF-\u03b1 release. The aims of this study were to analyze the molecular mechanisms of \u03b2-adrenergic downregulation and to explore therapeutic interventions with maintained anti-inflammatory efficacy in septic shock using the inhibition of phosphodiesterase 4 (PDE4).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>We conducted <jats:italic>in vitro<\/jats:italic> stimulation of peripheral blood mononuclear cells of healthy volunteers (n = 20) and patients with septic shock (n = 20) with lipopolysaccharide (LPS) or <jats:italic>Staphylococcus aureus<\/jats:italic> 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-\u03b1 production of untreated and stimulated CD14<jats:sup>+<\/jats:sup> monocytes. Protein expression of \u03b2-ARs, of G proteins, of adenylate cyclase, and of TLRs was measured by Western blotting.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Investigations were done by LPS (100 ng\/mL) or SEB (10 ng\/mL) when TLR4 and TLR2 were maximally expressed. LPS- or SEB-treated CD14<jats:sup>+<\/jats:sup> monocytes of healthy volunteers were able to produce TNF-\u03b1. This effect was attenuated by isoprenaline, forskolin, or rolipram in a concentration-dependent manner. In CD14<jats:sup>+<\/jats:sup> monocytes of patients with septic shock, the anti-inflammatory effect of isoprenaline was completely blunted whereas efficacy of forskolin and rolipram was maintained. CD14<jats:sup>+<\/jats:sup> monocytes of healthy volunteers were compared with patients with septic shock: protein expression of \u03b2<jats:sub>2<\/jats:sub>-ARs was reduced and inhibitory G protein was increased, whereas no changes in adenylate cyclase and stimulatory G protein were found.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>In septic shock, the anti-inflammatory effects of catecholamines are blunted by downregulation of \u03b2<jats:sub>2<\/jats:sub>-ARs and upregulation of the inhibitory G protein in CD14<jats:sup>+<\/jats:sup> 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.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/cc7158","type":"journal-article","created":{"date-parts":[[2008,12,17]],"date-time":"2008-12-17T19:14:10Z","timestamp":1229541250000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock"],"prefix":"10.1186","volume":"12","author":[{"given":"Andreas","family":"Link","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simina","family":"Selejan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Maack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"B\u00f6hm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2008,12,17]]},"reference":[{"key":"6572_CR1","doi-asserted-by":"publisher","first-page":"227","DOI":"10.7326\/0003-4819-113-3-227","volume":"113","author":"JE Parrillo","year":"1990","unstructured":"Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP: Septic shock in humans. 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