The epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) is important for the initiation of allergic airway inflammation through a dendritic cell-mediated T helper 2 response. To identify the factors that control TSLP expression, we examined the ability of inflammatory mediators to regulate TSLP production in human airway epithelial cells. We found that both IL-1 and TNF-␣ were capable of inducing rapid TSLP production in primary human bronchial airway epithelial cells. We further characterized the human TSLP gene promoter, using two human epithelial cell lines, 16HBEo ؊ and A549, and showed that IL-1-and TNF-␣-mediated human TSLP promoter activation in these cells was mediated by an upstream NF B site. Mutation of this NF B site abolished activation, as did overexpression of a dominant-negative version of I B kinase (IKK) (a kinase acting on I B, the inhibitor of NF B). Interestingly, human TSLP mRNA levels were also increased after exposure to Toll-like receptor (TLR) 2, TLR8, and TLR9 ligands, further supporting an important role for NF B in TSLP gene regulation. Similarly, analysis of the mouse TSLP gene promoter revealed the presence of a similarly situated NF B site that was also critical for IL-1-inducible expression of mouse TSLP. Taken together, these results demonstrate that the inflammatory mediators IL-1 and TNF-␣ regulate human TSLP gene expression in an NF B-dependent manner.proinflammatory cytokine ͉ T helper 2 inflammation ͉ transcriptional regulation T hymic stromal lymphopoietin (TSLP) is a cytokine that was originally identified in culture supernatants of a mouse thymic stromal cell line and has been shown to support the development of pre-B cells to B220 ϩ IgM ϩ immature B cells (1-4). The TSLP receptor complex is a heterodimer that consists of a low-affinity ligand binding chain, the TSLP receptor (TSLPR), and the IL-7 receptor ␣ chain (IL-7R␣) (5, 6). TSLP and TSLPR have also been identified and characterized in humans, and the human TSLP receptor complex has been shown to also be a heterodimer that is composed of the TSLPR and IL-7R␣ chains (7,8). Although the degree of sequence homology between human and mouse TSLP and between human and mouse TSLPR is quite low (43% and 39%, respectively), the expression profiles are similar in the two species, with B cells and CD11c ϩ dendritic cells being the primary cell populations expressing the TSLPR (ref. 9 and S.F.Z. and D. R. J. Rawlings, unpublished results). TSLP is produced primarily by epithelial cells in the lungs, gut, and skin (8). Recent work (e.g., refs. 10 and 11) has shown that TSLP levels are increased at sites of inflammation. For example, lesional skin from patients with atopic dermatitis displayed markedly elevated TSLP expression, whereas uninvolved skin did not (10). Similarly, airway epithelium from asthmatics showed increased TSLP mRNA expression (11) and supported a role for TSLP in promoting T helper 2-type allergic inflammation. CD4 ϩ T cells, primed by TSLP-treated dendritic cells, produce the proallergic cy...
The cytokine thymic stromal lymphopoietin (TSLP) has been implicated in the development and progression of allergic inflammation in both humans and mice. TSLP has been shown to promote Th2-type response through upregulation of OX40L on dendritic cells, and through direct induction of IL-4 production in naïve CD4 T cells. However, its direct effect on effector Th cells has not been extensively investigated. In this study, we show that the level of TSLPR expression on mouse effector Th2 cells is higher than on Th1 and Th17 cells, and that TSLP induced proliferation of effector Th2, but not Th1 and Th17 cells. TSLP also induced the phosphorylation of Signal Transducer and Activator of Transcription (Stat) 5, and expression of anti-apoptotic factor Bcl-2 in Th2 cells. Finally, TSLP-mediated proliferation on Th2 cells was enhanced by TCR stimulation, through IL-4-mediated induction of TSLPR expression. Taken together, these results indicate that TSLP is involved in exacerbation of mouse Th2-mediated allergic inflammation in a Th2 environment through direct stimulation of Th2 effector cells.
The hepatitis C virus (HCV) infects ~200 million people worldwide. The majority of infected individuals develop persistent infection, resulting in chronic inflammation and liver disease, including cirrhosis and hepatocellular carcinoma. HCV’s ability to establish persistent infection is partly due to its ability to evade the immune response through multiple mechanisms, including suppression of natural killer (NK) cells. NK cells control HCV replication during the early phase of infection and regulate the progression to chronic disease. In particular, IFN-γ produced by NK cells limits viral replication in hepatocytes and is important for the initiation of adaptive immune responses. However, NK cell function is significantly impaired in chronic HCV patients. The cellular and molecular mechanisms responsible for impaired NK cell function in HCV infection are not well defined. Here, we analyzed the interaction of human NK cells with CD33+ PBMCs that were exposed to HCV. We found that NK cells co-cultured with HCV-conditioned CD33+ PBMCs produced lower amounts of IFN-γ, with no effect on granzyme B production or cell viability. Importantly, this suppression of NK cell-derived IFN-γ production was mediated by CD33+CD11bloHLA-DRlo myeloid derived suppressor cells (MDSCs) via an arginase-1-dependent inhibition of mTOR activation. Suppression of IFN-γ production was reversed by L-arginine supplementation, consistent with increased MDSC arginase-1 activity. These novel results identify the induction of MDSCs in HCV infection as a potent immune evasion strategy that suppresses anti-viral NK cell responses, further indicating that blockade of MDSCs may be a potential therapeutic approach to ameliorate chronic viral infections in the liver.
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