LLT1-mediated activation of IFN-gamma production in human natural killer cells involves ERK signalling pathway.

Natural killer (NK) cell functions are regulated by a delicate balance of signals received through activating and inhibitory receptors expressed on the cell surface. Lectin-like transcript-1 (LLT1), expressed on a subpopulation of NK cells and other immune cells is a ligand for the NK cell inhibitory receptor, NKR-P1A (CD161). Previous studies showed that cross-linking surface LLT1 with a monoclonal antibody stimulated NK cell IFN-gamma secretion but had no effect on cytotoxicity. Here, we have examined the signalling pathways associated with LLT1-stimulated IFN-gamma secretion. We ligated LLT1 on NK92 cells with CD161 on target cells and analysed IFN-gamma production in the presence of pharmacological inhibitors specific for various signalling mechanisms. These results indicate that LLT1 employs Src-PTK, p38 and ERK signalling pathways, but not PKC, PI3K or calcineurin. Phosphorylation studies of the signalling adaptor molecules confirmed that the ERK signalling pathway is associated with LLT1-mediated IFN-gamma production. LLT1 ligation is not associated with any change in detectable IFN-gamma mRNA levels suggesting that LLT1-stimulated IFN-gamma production in NK cells may involve post-transcriptional or translational events.

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus.

CS1 (CRACC, CD319) and 2B4 (CD244), members of the signalling lymphocyte activation molecule (SLAM) family receptors, regulate various immune functions. Genes encoding SLAM family receptors are located at 1q23, implicated in systemic lupus erythematosus (SLE). In this study, we have investigated the expression and alternative splicing of CS1 and 2B4 in immune cells from SLE patients. The surface expression of CS1 and 2B4 on total peripheral blood mononuclear cells (PBMCs), T, B, natural killer (NK) cells and monocytes in 45 patients with SLE and 30 healthy individuals was analysed by flow cytometry. CS1-positive B cell population was increased significantly in SLE patients. Because CS1 is a self-ligand and homophilic interaction of CS1 induces B cell proliferation and autocrine cytokine secretion, this could account for autoreactive B cell proliferation in SLE. The proportion of NK cells and monocytes expressing 2B4 on their surface was significantly lower in patients with SLE compared to healthy controls. Our study demonstrated altered expression of splice variants of CS1 and 2B4 that mediate differential signalling in PBMC from patients with SLE.

Regulation of uterine contraction: mechanisms in preterm labor.

Preterm labor (PTL) is defined as uterine irritability accompanied by cervical dilation and/or effecement that occurs before 37 weeks gestation. In most cases, PTL becomes preterm delivery (PTD), accounting for 8% to 10% of births in the United States. Fetuses born before 37 weeks' gestation are at risk for a multitude of health and developmental problems. Most perinatal morbidity and mortality in the United States are caused by PTL. It is a costly problem, in both monetary and human terms. Although some risk factors have been identified, they by no means identify, in advance, every case of PTL and PTD. Despite the understandable emphasis on attempts to find and test risk factors that predict PTL, the ultimate benefit--preventing PTD--will come only from an understanding of the physiologic mechanisms of parturition and how to halt those processes when they occur too early. This article reviews current approaches to preventing PTD, describes the biology of myometrial contraction, and discusses recent progress from several laboratories including the authors' that may shed light on approaches to inhibit uterine contractility in the setting of PTL.