title: Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis.
abstract: Enhanced adrenergic stimulation and catecholamine release are important components of the pathophysiology of sepsis. Under physiological conditions, adrenergic stimulation has been shown to be a negative regulator of proinflammatory cytokine production through increasing IL-10 production. Here we have investigated if adrenergic stimulation similarly inhibits TNF-alpha and IL-6 production by splenic macrophages isolated from a polymicrobial sepsis model. Male B(6)D(2)F(1) mice were subjected to sham (S), laparotomy (Lap), and cecal ligation and puncture (CLP) under anesthesia. Splenic macrophages were isolated 72 h after the initial injury and were stimulated with endotoxin (LPS) in the presence and absence of epinephrine. Compared with S and Lap, splenic macrophages from the CLP group produced significantly less TNF-alpha and IL-6 and more IL-10 when stimulated with LPS. Macrophage cultures from CLP animals incubated with either epinephrine or IL-10 for 2 h had significantly reduced TNF-alpha and IL-6 release in response to LPS. However, similar cultures pretreated with IL-10 antibody before the addition of exogenous epinephrine failed to reverse the attenuation of LPS-stimulated cytokines. Pretreatment of macrophage cultures with beta(2)- (ICI-118551) but not beta(1)-adrenergic (atenolol) receptor antagonists reversed the epinephrine-mediated cytokine attenuation following LPS treatment. Data are also presented that demonstrate the involvement of protein kinase A activation with adrenergic agonist but not with IL-10 stimulation. Taken together, these findings suggest that adrenergic mechanisms may influence peripheral tissue macrophage inflammatory cytokine response following trauma and sepsis, independent of the effects of IL-10.
authors.affiliation: Department of Physiology, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Deng
authors.forename: Kuzhali
authors.initials: K
authors.lastname: Muthu
authors.forename: Richard
authors.initials: R
authors.lastname: Gamelli
authors.forename: Ravi
authors.initials: R
authors.lastname: Shankar
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Jones
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004731:Endotoxins / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D004837:Epinephrine / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018805:Sepsis / Q000276:immunology / Q000503:physiopathology*; D013154:Spleen / Q000276:immunology* / Q000378:metabolism
chemical_list: D000322:Adrenergic Agonists; D000319:Adrenergic beta-Antagonists; D016207:Cytokines; D004731:Endotoxins; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine