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RECEPTORS AND SIGNAL TRANSDUCTION

Propofol inhibits pressure-stimulated macrophage phagocytosis via the GABA_A receptor and dysregulation of p130cas phosphorylation

¹John D. Dingell Veterans Affairs Medical Center, and ²Department of Anesthesiology, Wayne State University, Detroit; and ³Department of Surgery, Michigan State University, Lansing, Michigan

Submitted 3 July 2008 ; accepted in final form 24 March 2009

Surgical stress and anesthesia result in systemic immunosuppression. Propofol, a commonly used anesthetic agent, alters immune cell functions. Previously, we demonstrated that extracellular pressure increases macrophage phagocytosis. We hypothesized that propofol might influence pressure-induced macrophage phagocytosis in monocytes from patients undergoing surgery. Pressure (20 mmHg above ambient pressure) augmented phagocytosis in monocytes from non-propofol-anesthetized patients but reduced phagocytosis in monocytes from propofol-anesthetized patients. In vitro, propofol stimulated phagocytosis but reversed pressure-induced phagocytosis in THP-1 macrophages and monocytes from healthy volunteers. The GABA_A receptor antagonists picrotoxin and SR-95531 did not affect basal THP-1 phagocytosis or prevent pressure-stimulated phagocytosis. However, picrotoxin and SR-95531 negated the inhibitory effect of pressure in propofol-treated cells without altering propofol-induced phagocytosis. Phosphorylation of the adaptor protein p130cas was inversely related to phagocytosis: it was inhibited by pressure or propofol but increased by pressure + propofol compared with propofol alone. Reduction of p130cas by small interfering RNA in THP-1 macrophages increased basal phagocytosis and prevented pressure and propofol effects. In conclusion, propofol may alter macrophage responses to pressure via the GABA_A receptor and p130cas, whereas pressure also acts via p130cas but independently of GABA_A receptors. p130cas may be an important target for modulation of macrophage function in anesthetized patients.

anesthesia; mechanotransduction; monocyte