IL-2 and Related Cytokines Can Promote T Cell Survival by Activating AKT

Kelly, Erin; Won, A Jin; Refaeli, Yosef; Parijs, Luk Van

doi:10.4049/jimmunol.168.2.597

Cited by 91 publications

(48 citation statements)

References 71 publications

(47 reference statements)

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“…Recently, we found that IL-2, a potent stimulus of lymphocytes (53,54), up-regulated P-glycoprotein expression on lymphocytes via activation of transcriptional factor YB-1 and that such up-regulation markedly reduced intracellular corticosteroid concentration in vitro (13). In this study, we found that 6.9-kDa fragmented hyaluronan was also a potent stimulus of CD4ϩ T cells as well as IL-2.…”

Section: Discussionsupporting

confidence: 49%

Fragmented Hyaluronan Induces Transcriptional Up-regulation of the Multidrug Resistance-1 Gene in CD4+ T Cells

Tsujimura

Saito

Kohno

et al. 2006

Journal of Biological Chemistry

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P-glycoprotein, encoded by the multidrug resistance (MDR)-1 gene, expels various drugs from cells resulting in multidrug resistance. We found previously that interleukin-2, a lymphocyte-activation cytokine, induces P-glycoprotein expression on lymphocytes. Lymphocyte activation involves adhesion with the extracellular matrix, such as hyaluronan, through adhesion molecules on lymphocytes. We investigated the transcriptional regulation of MDR-1 in lymphocytes by fragmented hyaluronan. Fragmented hyaluronan (especially the 6.9-kDa form), not native high molecular hyaluronan, induced translocation of YB-1, a specific transcriptional factor for MDR-1, from the cytoplasm into the nucleus and resulted in the transcription of MDR-1 and the expression of P-glycoprotein on lymphocytes in a dose-dependent manner. Transfection of YB-1 antisense oligonucleotides inhibited P-glycoprotein expression induced by fragmented hyaluronan. The fragmented hyaluronan induced significant P-glycoprotein expression on only activated CD4؉ T cells, which highly expressed CD69, and resulted in excretion of intracellular dexamethasone added in vitro. Cyclosporin A, a competitive P-glycoprotein inhibitor, restored intracellular dexamethasone levels in CD4؉ T cells. Anti-CD44 monoclonal antibody (Hermes-1) inhibited fragmented hyaluronan-induced YB-1 activation and P-glycoprotein expression in CD4؉ T cells. We provide the first evidence that binding of fragmented hyaluronan to CD44 induces YB-1 activation followed by P-glycoprotein expression in accordance with activation of CD4؉ T cells. Our findings imply that CD4؉ T cell activation by fragmented hyaluronan, induced by characteristic extracellular matrix changes in inflammation, tumors, and other conditions, results in P-glycoprotein-mediated multidrug resistance.

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Section: Discussionsupporting

confidence: 49%

Fragmented Hyaluronan Induces Transcriptional Up-regulation of the Multidrug Resistance-1 Gene in CD4+ T Cells

Tsujimura

Saito

Kohno

et al. 2006

Journal of Biological Chemistry

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“…In previous studies, it has been found that IL-2, a potent lymphocyte stimulus [31,32], upregulated the expression of P-gp on lymphocytes via activation of the transcription factor YB-1 and that this upregulation markedly reduced the intracellular CS concentration in vitro [33]. So, it may be a possibility that patients in nonresponder group have increased inflammatory cytokines leading to persistent P-gp expression and hence CS resistance.…”

Section: Discussionmentioning

confidence: 98%

Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus

et al. 2015

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Corticosteroids (CS) are the mainstay of treatment in systemic lupus erythematosus (SLE) patients. However, some patients have poor response to CS treatment. Among the multiple mechanisms of CS resistance, overexpression of P-glycoprotein (P-gp) on peripheral blood lymphocytes (PBL) may be one of them as this result in efflux of CS from lymphocytes. Thus, we evaluated the role of P-gp protein on PBLs in patients with SLE in its response to CS therapy. SLE patients (n = 42) (fulfilling ACR revised criteria) who were naïve to CS and immunosuppressive drugs were enrolled. Disease activity was assessed using SLE disease activity index (SLEDAI) and expression, and function of P-gp was evaluated by flow cytometry at baseline and after 3 months of therapy with CS. At 3 months, patients with SLEDAI >4 and SLEDAI ≤4 were grouped as nonresponders and responders, respectively. P-gp expression was significantly increased on PBLs of SLE patients as compared to healthy controls (p < 0.001). P-gp expression and function correlated with SLEDAI (r = 0.49, p = 0.005; and r = 0.49, p = 0.001, respectively). P-gp expression and function were not different in responders and nonresponders at baseline. However, at 3 months of CS therapy, P-gp expression and function decreased in responders (p < 0.001 and p < 0.005, respectively), whereas in nonresponders, it remained unchanged. Persistent overexpression and activity of P-gp are associated with poor response to CS in CS naïve patients of SLE.

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“…All of these pathways are known to up-regulate Bcl-2 and are modulated by redox signaling (45)(46)(47)(48)(49). CREB is an interesting candidate, because signaling through CREB is known to up-regulate Bcl-2 in B cells and T cells (50,51) and ROS inactivation of CREB can decrease Bcl-2 expression in neurons (8).…”

Section: Discussionmentioning

confidence: 99%

“…However, we have failed to observe a role for NF-B in suppression of Bcl-2 expression by using NF-B inhibitors (data not shown). Finally, PI-3K͞Akt signaling is a known pathway involved in Bcl-2 up-regulation in T cells (45,46). Endogenous antagonists of PI-3K can be activated by ROS, and inactivation of ROS leads to increased PI-3K signaling and prevention of apoptosis (53).…”

Section: Discussionmentioning

confidence: 99%

Control ofBcl-2expression by reactive oxygen species

Hildeman

Mitchell

Aronow

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

225

161

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Reactive oxygen species (ROS) are known to regulate cell death in a variety of cell types. Differential effects of ROS on cell death are observed depending on the level of ROS within the cell (1). High levels of ROS can lead to lipid peroxidation, damage to cellular membranes, inactivation of caspase enzymes, and necrotic cell death (1). In contrast, low levels of ROS have been shown to activate protein kinases and phosphatases, mobilize Ca 2ϩ stores, activate or inactivate transcription factors, and lead to apoptotic cell death (1). Thus, high levels of ROS probably kill cells by means of direct damage, whereas low levels of ROS probably mediate apoptosis indirectly through their effects on protein kinases and͞or phosphatases, transcription factors, and the subsequent effects of these molecules on gene expression. However, little has been done to assess the extent to which ROS affect gene expression in cells undergoing apoptosis.It has been known for some time that Bcl-2 overexpression can protect cells from apoptosis mediated by ROS (2). However, the mechanism by which Bcl-2 prevents ROS-induced apoptosis is unknown. Bcl-2 itself does not possess antioxidant activity; rather, it may act indirectly to increase the levels and͞or activities of endogenous antioxidants (e.g., glutathione or superoxide dismutase) within cells (3-5). Thus, overexpression of Bcl-2 may allow cells to cope better with the effects of ROS, possibly by allowing increases in endogenous antioxidant enzymes.An alternative but not mutually exclusive hypothesis is that ROS act to down-regulate endogenous Bcl-2 levels within cells. Because levels of Bcl-2 within cells are critical to antiapoptotic activity, decreasing Bcl-2 could be a mechanism to sensitize cells to apoptosis. By detoxifying ROS, antioxidants may therefore reverse the ROS-induced decline in Bcl-2 and prevent apoptosis. Several studies suggest a reciprocal relationship between ROS and Bcl-2 levels within cells (6-8). Thus, in divergent cell types, decreases in ROS correlate with increases in Bcl-2 levels and vice versa.Recently we showed that, in vivo, activated T cells decrease their levels of Bcl-2 and become susceptible to the proapoptotic effects of Bim (9). We also showed that culture of these activated T cells with a synthetic catalytic antioxidant, Mn(III) tetrakis(5,10,15,20-benzoic acid)porphyrin (MnTBAP), lowered superoxide levels and prevented apoptosis (10). Here, we show that culture of T cells with MnTBAP reverses the decline in Bcl-2. The corollary of this finding is that ROS are responsible for Bcl-2 down-regulation within activated T cells. Taken together, these results suggest a ''twosignal'' model for activated T cell apoptosis. The first signal is driven by ROS down-regulation of Bcl-2, which is necessary, but not sufficient, to complete apoptosis. The second signal requires the expression of Bim. . RNA extraction, cDNA synthesis, and gene microarray analysis were performed as described (11,12) Mice. C57BL͞10 and C57BL͞6J (BL͞6) mice were purchased from The Ja...

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IL-2 and Related Cytokines Can Promote T Cell Survival by Activating AKT

Cited by 91 publications

References 71 publications

Fragmented Hyaluronan Induces Transcriptional Up-regulation of the Multidrug Resistance-1 Gene in CD4+ T Cells

Fragmented Hyaluronan Induces Transcriptional Up-regulation of the Multidrug Resistance-1 Gene in CD4+ T Cells

Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus

Control ofBcl-2expression by reactive oxygen species

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