Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells.

Hama, Nobuaki; Paliogianni, Fotini; Fessler, Barri J.; Boumpas, Dimitrios T.

doi:10.1084/jem.181.3.1217

Cited by 43 publications

(30 citation statements)

References 26 publications

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“…However, the strong inhibition of FcyRI mRNA expression by cAMP, which only partially blocked STAT activation, suggests that additional pathways may be inhibited. These results show that at least two distinct major cellular signaling pathways that can inhibit immune responses (29)(30)(31)(32), those involving the serine protein kinases, calmodulin kinase, and protein kinase A, can inhibit STAT DNA-binding activity, and inhibition has important functional consequences for the expression of IL-6 regulated genes.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.

Sengupta

Schmitt

Ivashkiv

1996

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

122

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An important component of cytokine regulation of cell growth and differentiation is rapid transcriptional activation ofgenes by the JAK-STAT (signal transducer and activator of transcription) signaling pathway. Ligation of cytokine receptors results in tyrosine phosphorylation and activation of receptor-associated Jak protein tyrosine kinases and cytoplasmic STAT transcription factors, which then translocate to the nucleus. We describe the interruption of cytokine triggered JAK-STAT signals by cAMP, the calcium ionophore ionomycin, and granulocyte/macrophage colonystimulating factor. Jakl kinase activity, interleukin 6-induced gene activation, Stat3 tyrosine phosphorylation, and DNAbinding were inhibited, as was activation of Jakl and Statl by interferon y. The kinetics and requirement for new RNA and protein synthesis for inhibition of interleukin 6 by ionomycin and GM-CSF differed, but both agents increased the association of Jakl with protein tyrosine phosphatase ID (SH2-containing phosphatase 2). Our results demonstrate that crosstalk with distinct signaling pathways can inhibit JAK-STAT signal transduction, and suggest approaches for modulating cytokine activity during immune responses and inflammatory processes.An important advance in understanding the mechanism by which cytokines regulate cells has been the identification and characterization of the JAK-STAT (signal transducer and activator of transcription) signal transduction pathway (1-5). The binding of many cytokines and growth factors to their receptors activates Janus kinases (Jaks), which are protein tyrosine kinases that are physically associated with the receptor. Typically, stimulation by a particular cytokine results in the activation of a distinct pair of two of the four known Jaks. Jak kinases are required for tyrosine phosphorylation and activation of latent cytoplasmic transcription factors termed STATs. STATs are rapidly tyrosine phosphorylated after stimulation with cytokines, and subsequently dimerize and translocate to the nucleus, where they can activate transcription. v-Abl oncoproteins, and after ligation of the G proteincoupled angiotensin II receptor (9-12), suggest that signaling pathways in addition to those triggered by cytokines may be important in activation of STAT DNA-binding. Crosstalk and convergence with different signaling pathways, such as mitogen-activated protein kinase pathways, that regulate serine phosphorylation of STATs may be important for full activation of DNA-binding or transcriptional activity (13-16). Furthermore, cellular differentiation over several days or exposure to immune complexes can result in altered activation of the JAK-STAT pathway and altered cellular responses to cytokines (17-22). We have begun to explore whether cytokine activity can be modulated or inhibited by interrupting signaling through the JAK-STAT pathway. Our results show that several different signaling pathways can interrupt JAK-STAT signaling, likely at a proximal step, by inhibiting Jakl kinase activity. MATERIALS AND M...

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Section: Methodsmentioning

confidence: 99%

Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.

Sengupta

Schmitt

Ivashkiv

1996

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

122

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“…The functional relevance of this region is further supported by the recent identification of two intracellular proteins, namely, Tctex-1 and CaMK II␦ (31), which interact with a 33-aa peptide region containing T410 and T412. Tctex-1 is a dynein motor complex component (47), and CaMK II␦ is a serine/threonine kinase involved in IL-2 down-regulation (48), implying a role in CD5 internalization and negative signaling, respectively. Should these interactions be confirmed experimentally, it would be interesting to explore the role of the two threonines in the binding to Tctex-1 and CaMK II␦ (31).…”

Section: Figurementioning

confidence: 99%

Role of Two Conserved Cytoplasmic Threonine Residues (T410 and T412) in CD5 Signaling

Vila

Calvo

Places

et al. 2001

The Journal of Immunology

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CD5 is a transmembrane coreceptor that modulates activation and differentiation signals mediated by the Ag-specific receptor present on both T and B1a lymphocytes. CD5 lacks intrinsic catalytic activity, and its immunomodulatory properties result from intracellular interactions mediated by the CD5 cytoplasmic tail. The nature of these interactions is currently a matter of investigation. Here, we present a selective mutagenesis analysis of two conserved threonine residues (T410 and T412) located at the membrane-proximal cytoplasmic region of CD5. These residues are contained within consensus phosphorylation motifs for protein kinase C and are shown here to be critical for in vivo protein kinase C-mediated phosphorylation of CD5. Functional studies revealed that the integrity of T410 and T412 is also critical for CD5-mediated phosphatidylcholine-specific phospholipase C (PC-PLC) activation and phorbol ester-mediated inhibition of Ab-induced internalization of CD5. These results strongly argue in favor of a role for T410 and T412 in the signaling mediated by CD5.

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“…However, little information is available regarding the expression and function of CaMKII in T cells. Previous studies showed that constitutively active CaMKII␥B, CaMKII␥B T287D, blocked IL-2 and IL-4 promoter activities in Jurkat T cells, suggesting a role of CaMKII␥B in regulation of cytokine production (20,21). We have found that transgenic mice expressing CaMKII␥B T287D showed enhanced T cell activation and an increase in the proportion of memory T cells (22).…”

mentioning

confidence: 58%

“…The transfection of Jurkat T cells with CaMKII␥B T287D inhibited IL-2 and IL-4 promoter activity, suggesting a role of CaMKII␥B in the induction of T cell anergy (20,21). In contrast, we previously showed that there was an augmented response and an increase in memory CD4 and CD8 T cells in CaMKII␥B T287D transgenic mice (22).…”

Section: Discussionmentioning

confidence: 95%

“…Previous studies have shown that active CaMKII␥B blocked IL-2 and IL-4 production (20,21), and this would seem to counter the observed increase in proliferation. To examine production of cytokines in retrovirus-transduced T cells, we subjected the cells to intracellular IL-2 staining and IL-2 ELISA as depicted in Fig.…”

Section: The Enhanced Cd8 T Cell Proliferation Is Not Due To Cytokinementioning

confidence: 88%

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A Pivotal Role for the Multifunctional Calcium/Calmodulin-Dependent Protein Kinase II in T Cells: From Activation to Unresponsiveness

Lin

Żal

Ch’en

et al. 2005

The Journal of Immunology

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Stimulation of the TCR leads to an oscillatory release of free calcium that activates members of the calcium/calmodulin-dependent protein kinase II (CaMKII) family. The CaMKII molecules have profound and lasting effects on cellular signaling in several cell types, yet the role of CaMKII in T cells is still poorly characterized. In this report we describe a splice variant of CaMKIIβ, CaMKIIβ′e, in mouse T cells. We have determined its function, along with that of CaMKIIγ, by introducing the active and kinase-dead mutants into activated P14 TCR transgenic T cells using retroviral transduction. Active CaMKII enhanced the proliferation and cytotoxic activity of T cells while reducing their IL-2 production. Furthermore, it induced a profound state of unresponsiveness that could be overcome only by prolonged culture in IL-2. These results indicate that members of the CaMKII family play an important role in regulation of CD8 T cell proliferation, cytotoxic effector function, and the response to restimulation.

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Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells.

Cited by 43 publications

References 26 publications

Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.

Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways.

Role of Two Conserved Cytoplasmic Threonine Residues (T410 and T412) in CD5 Signaling

A Pivotal Role for the Multifunctional Calcium/Calmodulin-Dependent Protein Kinase II in T Cells: From Activation to Unresponsiveness

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