03483nas a2200601   4500000000100000008004100001260001600042653002700058653001700085653002100102653002000123653001400143653002500157653002000182653001800202653001100220653002000231653002400251653005000275653001200325653001200337653002600349653002500375653001500400653002200415653002900437653002800466653003400494653002800528653003100556653003000587653002400617653006500641653006200706653002600768653001400794653002100808653002600829100001500855700001600870700001800886700001400904700001400918700001500932700001600947700001500963700001500978245015100993300001101144490000801155520170401163022001402867       2004                            d  c2004 Sep 1510aAdjuvants, Immunologic10aAntigens, CD10aCarrier Proteins10aCells, Cultured10aCytokines10aDNA-Binding Proteins10aDown-Regulation10aGlycoproteins10aHumans10aImmunoglobulins10aIntracellular Fluid10aIntracellular Signaling Peptides and Proteins10aleprosy10aLigands10aLymphocyte Activation10aMycobacterium leprae10aNF-kappa B10aProtein Transport10aProtein-Tyrosine Kinases10aProto-Oncogene Proteins10aProto-Oncogene Proteins c-fyn10aReceptors, Cell Surface10aSTAT1 Transcription Factor10aSeverity of Illness Index10aSignal Transduction10aSignaling Lymphocytic Activation Molecule Associated Protein10aSignaling Lymphocytic Activation Molecule Family Member 110aT-Box Domain Proteins10aTh1 Cells10aTrans-Activators10aTranscription Factors1 aQuiroga MF1 aMartínez G1 aPasquinelli V1 aCostas MA1 aBracco MM1 aMalbrán A1 aOlivares LM1 aSieling PA1 aGarcía VE00aActivation of signaling lymphocytic activation molecule triggers a signaling cascade that enhances Th1 responses in human intracellular infection.  a4120-90 v1733 a<p>T cell production of IFN-gamma contributes to host defense against infection by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the disseminated form of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN-gamma production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN-gamma in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN-gamma production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN-gamma induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN-gamma production. However, SLAM ligation or exposure of cells from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover, SLAM activation induced a sequence of signaling proteins, including activation of the NF-kappaB complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion of IFN-gamma production, a pathway that remains quiescent in response to Ag in lepromatous patients. Therefore, our findings reveal a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce IFN-gamma production and strongly suggest that SLAM might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.</p>  a0022-1767