No abstract

TRAIL (also called Apo2L) belongs to the tumor necrosis factor family, activates rapid apoptosis in tumor cells, and binds to the death-signaling receptor DR4. Two additional TRAIL receptors were identified. The receptor designated death receptor 5 (DR5) contained a cytoplasmic death domain and induced apoptosis much like DR4. The receptor designated decoy receptor 1 (DcR1) displayed properties of a glycophospholipid-anchored cell surface protein. DcR1 acted as a decoy receptor that inhibited TRAIL signaling. Thus, a cell surface mechanism exists for the regulation of cellular responsiveness to pro-apoptotic stimuli.

Interleukin (IL)-17 is a pro-inflammatory cytokine that is produced by activated T cells. Despite increasing evidence that high levels of IL-17 are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis, and multiple sclerosis, the regulation of its expression is not well characterized. We observe that IL-17 production is increased in response to the recently described cytokine IL-23. We present evidence that murine IL-23, which is produced by activated dendritic cells, acts on memory T cells, resulting in elevated IL-17 secretion. IL-23 also induced expression of the related cytokine IL-17F. IL-23 is a heterodimeric cytokine and shares a subunit, p40, with IL-12. In contrast to IL-23, IL-12 had only marginal effects on IL-17 production. These data suggest that during a secondary immune response, IL-23 can promote an activation state with features distinct from the well characterized Th1 and Th2 profiles. Interleukin (IL)1 -17 is a T cell-derived pro-inflammatory molecule that stimulates epithelial, endothelial, and fibroblastic cells to produce other inflammatory cytokines and chemokines including IL-6, IL-8, G-CSF, and MCP-1 (1-8). IL-17 also synergizes with other cytokines including tumor necrosis factor-␣ and IL-1␤ to further induce chemokine expression (7, 9). Interleukin-17 levels are found to be significantly increased in rheumatoid arthritis synovium (10, 11), during allograft rejection (12-15), and in other chronic inflammatory diseases including multiple sclerosis (16) and psoriasis (17)(18)(19). Although clearly produced by activated T cells, previous reports have not provided clear classification of IL-17 within the paradigm of Th1 and Th2 polarized cytokine profiles.We have examined the possibility that IL-17 is expressed in response to signals distinct from those associated with the Th1 or Th2 response. We observe a previously unrecognized activity of the recently identified cytokine . IL-23 is a heterodimeric cytokine that shares one subunit, p40, with IL-12. The initial characterization of this cytokine has suggested it can promote proliferation within the memory T cell population. Subsequent work demonstrated that transgenic over-expression of the second component of IL-23, p19, was sufficient to induce systemic inflammation and premature death (21). In addition, the mice had markedly elevated levels of circulating neutrophils. Interestingly they did not exhibit consistent elevation of IFN-␥, a hallmark effect of IL-12. These data suggest that IL-23 may have a biological role substantially distinct from that of IL-12. In this report we present evidence that IL-23 acts to induce a distinct T cell activation state that produces IL-17 as a principle effector cytokine. EXPERIMENTAL PROCEDURESCell Culture-Single cell suspensions of spleen were prepared from C57/BL-6 mice, and mononuclear cells were isolated from suspended splenocytes by density gradient centrifugation. 2 ϫ 10 6 cells/ml were cultured with IL-2 (100 units/ml) in the presence or absence of vario...

Vertebrates and invertebrates initiate a series of defence mechanisms following infection by Gram-negative bacteria by sensing the presence of lipopolysaccharide (LPS), a major component of the cell wall of the invading pathogen. In humans, monocytes and macrophages respond to LPS by inducing the expression of cytokines, cell-adhesion proteins, and enzymes involved in the production of small proinflammatory mediators. Under pathophysiological conditions, LPS exposure can lead to an often fatal syndrome known as septic shock. Sensitive responses of myeloid cells to LPS require a plasma protein called LPS-binding protein and the glycosylphosphatidylinositol-anchored membrane protein CD14. However, the mechanism by which the LPS signal is transduced across the plasma membrane remains unknown. Here we show that Toll-like receptor 2 (TLR2) is a signalling receptor that is activated by LPS in a response that depends on LPS-binding protein and is enhanced by CD14. A region in the intracellular domain of TLR2 with homology to a portion of the interleukin (IL)-1 receptor that is implicated in the activation of the IL-1-receptor-associated kinase is required for this response. Our results indicate that TLR2 is a direct mediator of signalling by LPS.