Mycobacterial lipoarabinomannan affects human polymorphonuclear and mononuclear phagocyte functions differently

Background and Objectives. The role of mycobacterial lipoarabinomannan (LAM ) in regulating the granulomatous response and its effects on cells involve d in early responses to tuberculosis have not been clearly defined. The aim of this study was to acquire further evidence about the mechanisms by whic h LAM takes part in the host response to mycobacterial infections. Design and Methods. We compared the in vitro ability of mannosylated LAM (M anLAM) and LAM lacking the terminal mannosyl units (AraLAM) to induce disti nct responses in human polymorphonuclear (PMNs) and mononuclear phagocytes [both monocytes and 48-hr monocyte-derived macrophages (MDMs)]. The respons es examined were chemotaxis, transient changes in free cytosolic calcium, p hagocytosis and metabolic activation. Results. AraLAM and ManLAM affected mononuclear, but not polymorphonuclear, phagocyte functions. Both forms of LAM were chemotactic for monocytes and MDMs, The LAM-induced chemotactic response required new protein synthesis, did not induce a rise in cytosolic free calcium levels and was partially in hibited (about 50%) by genistein, but not by calphostin C or PD 98059, Last ly, at physiologic doses ManLAM significantly reduced phagocytosis of M. tu berculosis and zymosan particles by MDMs, Interpretation and Conclusions. Different phagocytic cells can exhibit vari able responses to AraLAM Bha ManLAM. Moreover, LAMs affect cell functions t hrough different mechanisms. Protein synthesis and activation of protein ty rosine kinases are important intermediates in the signal transduction pathw ay of the chemotactic response of mononuclear phagocytes to AraLAM and ManL AM; whereas ManLAM-induced inhibition of macrophage phagocytic ability coul d depend on the binding of macrophage man- nose receptors and/or the insert ion of this molecule into cellular plasma membrane. Together these data hig hlight the danger of making generalizations regarding the activity of LAMs on immune defenses. (C) 2000 Ferrata Storti Foundation.