RESUMEN
NK cells represent a large proportion of the lymphocyte population in the liver and are involved in early innate immunity to pathogen infection. As a result of liver endothelial cell fenestrations, parenchymal cells are not separated by a basal membrane, and thereby pathogen-infected hepatocytes are extensively capable of interacting with innate immune cells including NK cells. In addition, hepatic NK cells interact with surrounding DC and alter their differentiation and function. Recent studies reveal that NK cells exhibit a regulatory function that modulates T cell responses through their interaction with DC and/or direct effect on T cells. Thus, NK cells play a central role, not only in innate immunity, but also in shaping the adaptive immune response. During pathogen infection, there is a remarkable increase of hepatic NK cells, possibly due to the expansion of resident liver NK cells and/or recruitement of NK cells from the blood. The liver microenvironment is believed to modulate hepatic NK cell function through the induction of activating/inhibitory receptor expression and inflammatory cytokine secretion. Particularly, the liver maintains intrahepatic NK cells in a functionally hyporesponsive state compared to splenic NK cells: liver NK cells displayed a dampened IFN-γ response to IL-12/IL-18 stimulation. Notably, the liver contains a significant population of functionally hyporesponsive NK cells that express high levels of the inhibitory receptor NKG2A and lack expression of MHC class I-binding Ly49 receptors. Importantly, adoptively transferred splenic NK cells that migrate to the liver displayed phenotypic and functional changes, supporting a view that the liver environment modifies NK cell receptor expression and functional responsiveness. In this article, we will review studies on the regulation of NK cell repertoire and function in the hepatic environment and the impact of liver NK cell immunoregulatory function on influencing adaptive immunity.
Asunto(s)
Células Asesinas Naturales/inmunología , Hígado/inmunología , Inmunidad Adaptativa , Animales , Diferenciación Celular , Humanos , Células Asesinas Naturales/citología , Receptores de Células Asesinas Naturales/inmunologíaRESUMEN
Our studies in the RBL-2H3 mast cell line suggest that responses to antigen (Ag) are negatively modulated through upregulation of Src-like adaptor protein (SLAP). Ag stimulation of RBL-2H3 cells leads to increased levels of SLAP (but not SLAP2) transcripts and protein over a period of several hours. The effects of pharmacologic inhibitors indicate that the upregulation of SLAP is dependent on multiple signaling pathways. Knockdown of SLAP with anti-SLAP siRNA is associated with enhanced phosphorylation of Syk, the linker for activation of T cells (LAT), phospholipase C gamma, MAP kinases, and various transcription factors. Production of IL-3 and MCP-1, but not degranulation, is also enhanced. The upregulation of SLAP may thus serve to limit the duration of cytokine production in Ag-stimulated cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Antígenos/farmacología , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Regulación hacia Arriba/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Degranulación de la Célula/efectos de los fármacos , Citocinas/biosíntesis , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Mastocitos/fisiología , Fosforilación/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Receptores de IgE/inmunología , Transducción de Señal/efectos de los fármacosRESUMEN
Mast cells mediate both IgE-dependent allergic reactions and protective responses against acute infections, possibly through the activation of Toll-like receptors (TLRs). We find that antigen interacts synergistically with TLR2 and TLR4 ligands to markedly enhance production of cytokines in murine mast cell lines. However, the TLR ligands neither stimulated degranulation and release of arachidonic acid nor influenced such responses to antigen, probably because these ligands failed to generate a necessary calcium signal. The enhanced cytokine production could be attributed to synergistic activation of mitogen-activated protein kinases in addition to the engagement of a more effective repertoire of transcription factors for cytokine gene transcription. The synergistic interactions of TLR ligands and antigen might have relevance to the exacerbation of IgE-mediated allergic diseases by infectious agents.
Asunto(s)
Citocinas/metabolismo , Mastocitos/inmunología , Receptores de IgE/metabolismo , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Ácido Araquidónico/metabolismo , Calcio/metabolismo , Señalización del Calcio , Degranulación de la Célula , Células Cultivadas , Citocinas/genética , Citocinas/inmunología , Activación Enzimática , Quinasas Asociadas a Receptores de Interleucina-1 , Ligandos , Lipopolisacáridos/farmacología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas/metabolismoRESUMEN
OBJECTIVE: To clone the full-length cDNA of a gene responsible for vascular smooth muscle cell (v-SMC) proliferation in atherogenesis, and study its function. METHODS: Oxidized low density lipoprotein (ox-LDL) at optimal concentration was used as the stimulant to induce v-SMC proliferation in culture medium. A cDNA subtractive library of v-SMC proliferation specific to ox-LDL stimulation was established using subtractive hybridization technique. Methods, including blotting, Northern hybridization and gene sequencing, were used to clone new gene fragments. By using full-length cDNA screening and protein expression techniques, one full-length cDNA was cloned and its function was studied. RESULTS: One full-length cDNA was cloned. The new gene (Genbank AF 174647) expressed a 44 kDa protein, which might be associated with the activity of ox-LDL. CONCLUSION: The new gene cloned may be associated with SMC proliferation in atherogenesis.