Recombinant NFAT1 (NFATp) Is Regulated by Calcineurin in T Cells and Mediates Transcription of Several Cytokine Genes

Luo, Chun; Burgeon, Emmanuel; Carew, Josephine A.; McCaffrey, Patricia G.; Badalian, Tina M.; Lane, William S.; Hogan, Patrick G.; Rao, A. Nageswar

doi:10.1128/mcb.16.7.3955

Cited by 190 publications

(174 citation statements)

References 66 publications

(126 reference statements)

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“…Moreover, we had shown that Tpl-2 activates NFAT, a complex transcription factor composed of NFAT and AP1 components, whose activation is obligatory for IL-2 induction (Jain et al, 1992;Luo et al, 1996;Northrop et al, 1993;Rooney et al, 1995). Since Tpl-2 activates NFAT as well as the MAPK pathway (Ceci et al, 1997;Tsatsanis et al, 1998), which is required for the activation of AP1 (Jain et al, 1993), we examined whether dominant negative mutants of several proteins transducing signals along these pathways inhibit the activation of the IL-2 promoter by Tpl-2.…”

Section: Resultsmentioning

confidence: 99%

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

1998

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The Tpl-2 kinase activates the nuclear factor of activated T cells (NFAT) and induces IL-2 expression in T-cell lines. Here we show that the activation of the IL-2 promoter by Tpl-2 is inhibited by mutant signaling molecules that inhibit the mitogen-activated protein kinase (MAPK) or the calcineurin/NFAT pathways and is promoted by combinations of signaling molecules that activate these pathways. We, therefore, conclude that signals generated by the convergence of the MAPK and the calcineurin/NFAT pathway are necessary and su cient for the activation of the IL-2 promoter by Tpl-2. The activation of both the IL-2 promoter and an NFAT-driven minimal promoter were shown to depend on signals transduced by Raf1. However, it was only the IL-2 promoter whose activation by Tpl-2 was fully blocked by the dominant negative mutant MEK1S218/ 222A and the MEK1/MEK2 inhibitor PD098059. Since the activation of NFAT is MAPK-dependent these ®ndings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2. In addition, they suggested that the activation of the IL-2 promoter is under the control of not only NFAT but also a second factor whose activation is MEK-dependent. Experiments in COS-1 and EL-4 cells con®rmed both hypotheses and revealed that the second factor activated by Tpl-2 is NF-kB. While the activation of the IL-2 promoter and an NFAT-driven minimal promoter by Tpl-2 was fully blocked by the dominant negative mutant NFATD418, it was only partially blocked by the calcineurin inhibitor cyclosporin A suggesting that the Tpl-2-mediated NFAT activation is under the control of a combination of calcineurindependent and independent pathways. Both pathways were fully blocked by Bcl-2 or Bcl-X L .

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Section: Resultsmentioning

confidence: 99%

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

1998

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“…Rather, the integrated stimulation of PMA and a Ca 2ϩ influx results in activation of transcription factors of the NF-AT (NF of activated T cells) family in a CsA-sensitive manner (61)(62)(63). Our data suggest that in HBECs the addition of a Ca 2ϩ ionophore was modulatory, but was not required for PMA-stimulated generation of GM-CSF mRNA or protein.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Expression of Granulocyte-Macrophage Colony-Stimulating Factor in Human Bronchial Epithelial Cells: Roles of Protein Kinase C and Mitogen-Activated Protein Kinases

Reibman

Talbot

Hsu

et al. 2000

The Journal of Immunology

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GM-CSF has a major role in the immune and inflammatory milieu of the airway. Airway epithelial cells (AEC) are among the first targets of environmental stimuli and local cytokines, in response to which they can produce GM-CSF. The regulation of GM-CSF is only minimally understood in AEC. We hypothesized that GM-CSF expression in AEC would result from activation of protein kinase C (PKC) and subsequent activation of the extracellular signal-regulated kinase (MAPKerk1/2) pathway, so we investigated signal transduction pathways in human primary culture bronchial epithelial cells (HBECs). TNF-α, IL-1β, and PMA induced the release of GM-CSF in HBECs. The robust response to PMA was not detected in SV40 adenovirus-transformed normal human bronchial epithelial cells (BEAS-2B). PMA and TNF-α stimulation of GM-CSF required activation of PKC (inhibition by staurosporine and bisindolylmaleimide I). GM-CSF expression was up-regulated by a nonphorbol PKC activator, but not by an inactive PMA analogue. PMA-induced GM-CSF production in HBECs did not require a Ca2+ ionophore and was not inhibited by cyclosporin A. Activation of MAPKerk1/2 via PKC was associated with and was required for GM-CSF production induced by PMA and TNF-α. The data demonstrate regulation of GM-CSF in HBECs by PKC pathways converging on the MAPKerk1/2 pathway and further define cell-specific regulation critical for local airway responses.

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“…In some instances, the interaction of NF-B with other transcriptional proteins is required to activate transcription [9][10][11][12][13][14][15]. In addition, NF-B-independent pathways have been suggested to be involved in the induction of these proinflammatory genes [16][17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

Haas

Page

et al. 1998

Journal of Leukocyte Biology

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Abstract:We investigated the effect of proteasome inhibitors on the lipopolysaccharide (LPS)-induced expression of several monocytic cytokines, which may be dependent on the transcription factor, nuclear factor-B (NF-B). Exposure of human monocytic THP-1 cells to ALLN and Mu873 prevented the LPS-induced degradation of I B-␣ and -␤, as did the more potent proteasome inhibitor, PSI, whereas several calpain inhibitors were ineffective. This was accompanied by the inhibition of nuclear NF-B binding activity and NF-B transcriptional activation. At the mRNA level, the inhibitors blocked the expression of tumor necrosis factor (TNF) and interleukin-1␤ (IL-1␤), whereas IL-8 remained unaffected by ALLN and was only partially reduced by the highest dose of PSI. The latter effect appears to be due to an increase in IL-8 mRNA stability in the presence of proteasome inhibitors. Furthermore, the production of TNF was efficiently suppressed by ALLN and PSI, less by Mu873, and not at all by calpain inhibitors. In primary human blood monocytes ALLN also prevented the LPS-induced degradation of I B-␣ and -␤, efficiently blocked the production of TNF and, to a lesser extent, IL-1␤, whereas that of IL-8 was not inhibited. The expression of NF-B-dependent monocytic cytokines may be selectively controlled by the proteasome, offering a potential therapeutic target in inflammatory disease.

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Recombinant NFAT1 (NFATp) Is Regulated by Calcineurin in T Cells and Mediates Transcription of Several Cytokine Genes

Cited by 190 publications

References 66 publications

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

Regulation of Expression of Granulocyte-Macrophage Colony-Stimulating Factor in Human Bronchial Epithelial Cells: Roles of Protein Kinase C and Mitogen-Activated Protein Kinases

Effect of proteasome inhibitors on monocytic IκB-α and -β depletion, NF-κB activation, and cytokine production

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