Differential tolerance induction by lipoarabinomannan and lipopolysaccharide in human macrophages

Various bacterial cell wall components have been shown to induce hyporespon siveness in macrophages (MAC). Here, mycobacterial glycolipids were employe d to determine whether they induce a state of 'tolerance/hyporesponsiveness ' in MAC in vitro in order to assess whether mycobacterial components negat ively affect the immune response to Mycobacterium tuberculosis. Arabinosyla ted lipoarabinomannan (ARA-LAM) stimulated hyporesponsiveness by reducing T NF-cr, GM-CSF, G-CSF, IL-10, and IL-6 release similarly to LPS, but caused no changes in IL-8 secretion. Mannose-capped LAM (MAN-LAM) acted in a diffe rent way in that TNF-a, GM-CSF, and IL-10 were upregulated after restimulat ion of MAC. Blocking experiments by mannan suggest mannose-receptor involve ment in MAN-LAM activation only. Cross-stimulation experiments demonstrated a hierarchy of signaling, with LPS being the most potent stimulator and me diating abrogation of ARA-LAM-stimulated tolerance but not vice versa. MAN- LAM was the least potent stimulator of either MAC activation and induction of hyporesponsiveness. Similarly to LPS, ARA-LAM upregulated CD 14 surface expression after restimulation. Recurrent MAN-LAM treatment either downmodu lated or did not induce any change in CD14 expression. The role of MAN-LAM regulated cytokine secretion as well as implications regarding M. tuberculo sis infection will be discussed. (C) 2000 Editions scientifiques et medical es Elsevier SAS.