Propofol inhibits pressure-stimulated macrophage phagocytosis via the GABAA receptor and dysregulation of p130cas phosphorylation.
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.
John D. Dingell Veterans Affairs Medical Center, Detroit, Michigan, USA.
Hiroe
H
Shiratsuchi
Yasser
Y
Kouatli
Guang Xiang
GX
Yu
Harold M
HM
Marsh
Marc D
MD
Basson
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D002460:Cell Line; D050719:Crk-Associated Substrate Protein / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects*; D010766:Phosphorylation; D010852:Picrotoxin / Q000494:pharmacology; D011312:Pressure; D015742:Propofol / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013314:Stress, Mechanical; D013997:Time Factors
D018686:Anesthetics, Intravenous; D050719:Crk-Associated Substrate Protein; D018756:GABA Antagonists; D010852:Picrotoxin; D015742:Propofol; D011724:Pyridazines; D034741:RNA, Small Interfering; D011963:Receptors, GABA-A; C493841:BCAR1 protein, human; C049853:gabazine