ABSTRACT
The present study was undertaken to investigate the possible role of a 10-kDa, secretory antigenic protein of Mtb (MTSA-10) in regulating macrophase response to lipopolysacchride (LPS). MTSA-10 inhibited the lipopolysaccharide (LPS)-induced oxidant species generation in the macrophage. Treatment of macrophages with MTSA-10 activated their protein tyrosine phosphatases (PTPs) in a redox-regulated fashion. These activated phosphatases then interfered with the early events of LPS signaling and lower the strength and magnitude of the signal generated, thereby preventing macrophages from making an effective immune response. Mycobacterium tuberculosis Region of Deletion-1 (RD-1)-specific secretory antigen MTSA-10 (encoded by ORF Rv3874 of Mtb genome) modulated the macrophage signaling machinery and prevented it from responding to further activation by LPS.
Subject(s)
Bacterial Proteins/pharmacology , Lipopolysaccharides/pharmacology , Macrophages, Peritoneal , Mycobacterium tuberculosis , Phosphoric Monoester Hydrolases/metabolism , Animals , Bacterial Proteins/immunology , Cell Line , Humans , Lipopolysaccharides/immunology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Mice , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/immunology , Oxidation-Reduction , Reactive Oxygen Species/metabolism , Signal Transduction/physiologyABSTRACT
Activation of cell-surface receptors stimulates generation of intracellular signals that, in turn, direct the cellular response. However, mechanisms that ensure combinatorial control of these signaling events are not well understood. We show here that the Ca2+ and reactive oxygen intermediates generated upon BCR activation rapidly engage in a cooperative interaction that acts in a feedback manner to amplify the early signal generated. This cooperativity acts by regulating the concentration of the oxidant produced. The latter exerts its influence through a pulsed inactivation of receptor-coupled phosphatases, where the amplitude of this pulse is determined by oxidant concentration. The extent of phosphatase inhibition, in turn, dictates what proportion of receptor-proximal kinases are activated and, as a result, the net strength of the initial signal. It is the strength of this initial signal that finally determines the eventual duration of BCR signaling and the rate of its transmission through downstream pathways.
