| JWissmille 2004-11-10, 4:08 am |
| http://www.ncbi.nlm.nih.gov/entrez/...db=PubMed&list_
uids=15356162&dopt=Abstract
J Immunol. 2004 Sep 15;173(6):4120-9.
*Activation of signaling lymphocytic activation molecule triggers a
signaling cascade that enhances Th1 responses in human intracellular
infection.*
*Quiroga MF, Martinez GJ, Pasquinelli V, Costas MA, Bracco MM, Malbran
A, Olivares LM, Sieling PA, Garcia VE.*
Department of Microbiology, Parasitology, and Immunology, university of
Buenos Aires School of Medicine, Buenos Aires, Argentina.
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. Copyright 2004
The American Association of Immunologists, Inc.
PMID: 15356162 [PubMed - indexed for MEDLINE]
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