title: Pulmonary surfactant inhibits monocyte bactericidal functions by altering activation of protein kinase A and C.
abstract: Pulmonary surfactant, the main function of which is to reduce surface tension in the alveoli, is also known to affect the functions of monocytes. Two protein kinases play a role in the regulation of the bactericidal functions of phagocytes, i.e. cAMP-dependent protein kinase A (PKA), which is involved in inhibition, and Ca2+/phospholipid-dependent PKC, which is involved in stimulation of these functions. In the present study we investigated whether altered activation of PKA and/or PKC plays a role in the surfactant-induced inhibition of both the intracellular killing of Staphylococcus aureus and the production of reactive oxygen intermediates (ROI) by monocytes. The significance of increased activation of PKA was demonstrated by the following findings. Firstly, surfactant induced a sustained increase in the intracellular cAMP concentration in monocytes. Secondly, dibutyryl-cAMP (db-cAMP), a membrane-permeable cAMP analogue, mimicked the inhibitory effects of surfactant on both the killing capacity and the production of ROI by monocytes. Thirdly, an inhibitor of PKA partially restored the impaired bactericidal functions of monocytes incubated with surfactant. The involvement of decreased activation of PKC in the impaired bactericidal functions of monocytes incubated with surfactant was evident from two findings. Firstly, surfactant attenuated the phorbol myristate acetate (PMA)-mediated translocation of PKC. Secondly, surfactant inhibited the production of O2- by monocytes upon stimulation with PMA. Therefore, the mechanism involved in the surfactant-induced inhibition of the bactericidal functions of monocytes comprises both activation of an inhibitory pathway, which includes cAMP and PKA, and inactivation of a stimulatory pathway, in which PKC is involved.
authors: Department of Infectious Diseases, University Hospital Leiden, The Netherlands.
authors: M F
authors: MF
authors: Geertsma
authors: T P
authors: TP
authors: Zomerdijk
authors: P H
authors: PH
authors: Nibbering
authors: R
authors: R
authors: van Furth
mesh_terms: D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D047428:Protein Kinase Inhibitors; D011663:Pulmonary Surfactants / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology*; D013449:Sulfonamides
chemical_list: D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011663:Pulmonary Surfactants; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium