NKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection.
In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells, particularly NK cells and other immune cells that express germline-encoded receptors that are often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression are summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion of some of the implications of the various findings with respect to possibly therapeutic approaches.
fit of the cytokine treatment in mice with RMA-S tumors was completely abrogated if the mice were NK-depleted, demonstrating that the effect of the cytokines depended on NK cells ( Figure 1C).The efficacy of cytokine treatments in mice bearing RMA-S tumors did not apply to mice bearing RMA tumors, which are similar to RMA-S cells except that they express high amounts of MHC class I and are therefore resistant to NK cells ( Figure 1B, bottom panel). The survival time in mice with RMA tumors did not change when the mice were treated with cytokines, and was similarly rapid to that in untreated mice with RMA-S tumors.Recently, Levin and colleagues described the "superkine" H9, an engineered version of IL-2, which functions independently of the α chain (CD25) of the IL-2 receptor. Compared with WT IL-2, H9 exhibits much more activity on NK cells and T cells. In vivo, H9 stimulated rejection of B16F10 melanoma tumors in B6 mice (13), but the role of NK cells in rejection has not been investigated. We tested whether H9 induces NK-dependent rejection of MHC class I-deficient tumors by implanting high doses of RMA-S or RMA cells and initiating H9 treatment after 7 days. Similar to the results with IL-12+IL-18 treatment, H9 resulted in improved survival of RMA-S-bearing mice, but had no effect in RMA-bearing mice (Figure 2, A and B). Notably, when mice were depleted of NK cells, the efficacy of H9 treatment was abolished (Figure 2A). These results show that H9 exerts its antitumor effect against MHC class I-deficient tumor cells in an NK cell-dependent fash-
The administration of mesenchymal stem cells (MSCs) has been proposed for the treatment of pulmonary hypertension. However, the effect of intratracheally administered MSCs on the pulmonary vascular bed in monocrotaline-treated rats has not been determined. In the present study, the effect of intratracheal administration of rat MSCs (rMSCs) on monocrotaline-induced pulmonary hypertension and impaired endothelium-dependent responses were investigated in the rat. Intravenous injection of monocrotaline increased pulmonary arterial pressure and vascular resistance and decreased pulmonary vascular responses to acetylcholine without altering responses to sodium nitroprusside and without altering systemic responses to the vasodilator agents when responses were evaluated at 5 wk. The intratracheal injection of 3 x 10(6) rMSCs 2 wk after administration of monocrotaline attenuated the rise in pulmonary arterial pressure and pulmonary vascular resistance and restored pulmonary responses to acetylcholine toward values measured in control rats. Treatment with rMSCs decreased the right ventricular hypertrophy induced by monocrotaline. Immunohistochemical studies showed widespread distribution of lacZ-labeled rMSCs in lung parenchyma surrounding airways in monocrotaline-treated rats. Immunofluorescence studies revealed that transplanted rMSCs retained expression of von Willebrand factor and smooth muscle actin markers specific for endothelial and smooth muscle phenotypes. However, immunolabeled cells were not detected in the wall of pulmonary vessels. These data suggest that the decrease in pulmonary vascular resistance and improvement in response to acetylcholine an endothelium-dependent vasodilator in monocrotaline-treated rats may result from a paracrine effect of the transplanted rMSCs in lung parenchyma, which improves vascular endothelial function in the monocrotaline-injured lung.
To test the hypothesis that MSCs alone or endothelial nitric oxide synthase (eNOS)-modified MSCs can be used for treatment of erectile dysfunction (ED), syngeneic rat MSCs (rMSCs) were isolated, ex vivo expanded, transduced with adenovirus containing eNOS, and injected into the penis of aged rats. Histological analysis demonstrated that rMSCs survived for at least 21 days in corporal tissue after intracavernous injection, and an inflammatory response was not induced. Intracavernous administration of eNOSmodified rMSCs improved the erectile response in aged rats at 7 and 21 days after injection. The increase in erectile function was associated with increased eNOS protein, NOS activity, and cGMP levels. rMSCs alone increased erectile function of aged rats at day 21, but not at day 7, with the transplanted cells exhibiting positive immunostaining for several endothelial and smooth muscle cell markers. This change in rMSC phenotype was accompanied by upregulation of penile eNOS protein expression/activity and elevated cGMP levels. These findings demonstrate that an adenovirus can be used to transduce ex vivo expanded rMSCs to express eNOS and that eNOS-modified rMSCs improve erectile function in the aged rat. Intracavernous injection of unmodified wildtype rMSCs improved erectile function 21 days after injection through mechanisms involving improved endotheliumderived NO/cGMP signaling and rMSC differentiation into penile cells expressing endothelial and smooth muscle markers. These data highlight the potential clinical use of adult stem cell-based therapy for the treatment of ED. endothelium; gene therapy; cGMP; phosphodiesterase type 5; neuronal nitric oxide synthase PENILE ERECTION IS A COMPLEX neurovascular response that requires an increase in arterial inflow, relaxation of corporal smooth muscle, and restriction of venous outflow (29,35). Relaxation of corporal smooth muscle is essential for normal erectile activity, and evidence has accumulated to implicate nitric oxide (NO) as a major mediator of corporal smooth muscle relaxation and penile erection (14, 44). The release of NO from the endothelium and nitrergic nerves innervating the penile vasculature serves to activate NO-sensitive guanylyl cyclase and increase penile tissue cGMP levels. cGMP activates a cGMP-dependent protein kinase (PKG), and the phosphorylation of downstream proteins results in decreased intracellular calcium concentration and vasodilation (4). cGMP is subsequently hydrolyzed by type 5 phosphodiesterase (PDE5), and PDE5 inhibitors have been shown to successfully treat male erectile dysfunction (ED) (46).As men age, a significant decline in erectile function occurs (24, 41). Aging is recognized to alter endothelial cell function, and age-related impairments in erectile function have been attributed to multiple factors including increased penile vascular tone, endothelial dysfunction, and reduced NO bioavailability (4, 15, 27). The decreased NO bioavailability has been associated with the formation of reactive oxygen species (ROS), and, w...
Granzyme B expression is essential for eliciting NK cell cytotoxicity and T cell function. However, its transcriptional regulatory mechanism is not well understood. In this report, we demonstrate in human NK cells and T cells that the NF-κB-signaling pathway is involved in such control. Furthermore, a novel downstream human granzyme B gene sequence (GGAGATTCCC) was identified for NF-κB binding. EMSA, luciferase, and chromatin immunoprecipitation assays in vitro and in vivo indicated that this NF-κB binding site is functional in an NK cell line and its primary counterpart. Our data also demonstrate that this binding site is functional in Jurkat T cells. Taken together, we identified a novel NF-κB binding site, which plays a pivotal role in controlling human granzyme B gene transcription.
Induction of Type I IFNs is a central event in antiviral responses and must be tightly controlled. The protein kinase TBK1 is critically involved in virus-triggered type I IFN signaling. In this study, we identify an alternatively spliced isoform of TBK1, termed TBK1s, which lacks exons 3-6. Upon Sendai virus (SeV) infection, TBK1s is induced in both human and mouse cells and binds to RIG-1, disrupting the interaction between RIG-I and VISA. Consistent with that result, overexpression of TBK1s inhibits IRF3 nuclear translocation and leads to a shutdown of SeV-triggered IFN-␤ production. Taken together, our data indicate that TBK1s plays an inhibitory role in virus-triggered IFN-␤ signaling pathways.
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