Regulation of the Maintenance of Peripheral T-Cell Anergy by TAB1-Mediated p38α Activation

Ohkusu-Tsukada, Kozo; Tominaga, Norio; Udono, Heiichiro; Yui, Katsuyuki

doi:10.1128/mcb.24.16.6957-6966.2004

Cited by 41 publications

(32 citation statements)

References 49 publications

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“…1 T cells is dominant and a target for inhibition of both IL-10 production and unresponsiveness [14]. In the present study we found that depletion of CD25 1 Treg in combination with treatment with a p38 chemical inhibitor (p38-inhibitor) is necessary to completely block the immunosuppressive function of IL-10-producing anergic CD25 À iTreg, which suggested that a combination of treatment by both methods may be important to the success of peptide immunotherapy in cancer patients.…”

Section: Anergic Cd4mentioning

confidence: 56%

“…However, the suppressor function that is not mediated by IL-10 in the human iTreg may be distinguished to that of in vivo Ag-induced mouse iTreg. We now suspect that the dominant p38 activation in response to other MAPK (ERK and JNK) in in vivo Ag-induced iTreg is related to both the suppressor function via IL-10 production and the anergic state via cell cycle arrest and p27 expression and not via IL-10 [14]. Recent studies have indicated that p38 activation is required for TGF-b-induced in vitro conversion to iTreg [23,24] and is involved in IL-10 production via innate TLR2 signaling of HSP60 in iTreg [25] or in the induction to iTreg through tDC treated with CpG [26].…”

Section: Il-10-producing Cd25mentioning

confidence: 99%

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Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

et al. 2010

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Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1 a , into specific TCR Vb8.1-Tg mice enabled generation of anergic CD25À iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25 À iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25 1 Treg were present, suggesting that depletion of CD25 1 Treg is necessary for p38-inhibitor to be effective. Peptide OVA 323-339 iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25 1 Tregdepletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25 À iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25 1 Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.

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Section: Anergic Cd4mentioning

confidence: 56%

Section: Il-10-producing Cd25mentioning

confidence: 99%

Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

et al. 2010

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“…33 p38 MAPK activation by IL-24 and other factors, such as TGF-b, 34 may also contribute to anergy in CLL similarly to that demonstrated in T cells. 35 Since Mda-7 promoted cell survival, it could be expected that its expression level correlates with the clinical/biological status in CLL, and a quantitative study of Mda-7 and phospho-p38 MAPK should be carried out, although in preliminary studies we failed to observe a difference between Ig-mutated vs unmutated patients. The same question should be addressed for CD5.…”

Section: Discussionmentioning

confidence: 99%

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

et al. 2006

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Chronic lymphocytic leukemia (CLL)-B-cells are quiescent differentiated cells that produce interleukin (IL)-10 and accumulate due to resistance to apoptosis. The mechanisms underlying such resistance are poorly understood. Herein we show that all CLL B-cells tested (30/30) display high mRNA and protein expression of the tumor suppressor Mda-7/IL-24, an IL-10 family member, in comparison to normal B cells. A downstream Mda-7 signaling target, p38 mitogen-activated protein kinase (MAPK) was highly phosphorylated in all CLL cells but not in normal B-cells. Mda-7 expression and p38 MAPK phosphorylation diminished in culture and the latter could be reinduced by recombinant (r)-IL-24 or LPS and Mda-7 transfection. Mda-7/IL-24 siRNA specifically inhibited p38 MAPK phosphorylation in CLL without affecting p38 MAPK, bcl2, or Lyn expression, further demonstrating the direct role of Mda-7/ IL-24 in p38 MAPK activation. Both pharmacological inhibition of p38 MAPK and Mda-7 silencing augmented spontaneous apoptosis by three-fold in CLL cells cultured in autologous serum, which was reversed by LPS and r-IL-24. We established the role of p38 MAPK in CLL cell survival and demonstrated a paradoxical effect, whereby Mda-7 and IL-24, inducers of apoptosis in diverse cancer cells, promote the survival of CLL B-cells through p38 MAPK activation.

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“…Although there is an indication that TAB1-dependent p38 phosphorylation occurs in LPS, TNF, and CpG treated B cell lines, a study using MKK3/6 knockout MEF cells showed that TNFinduced p38 activation is solely dependent on MKKs [29]. While the biological contexts of MKK-independent p38 activation still need further investigation, there is a couple of recent publications that support the role TAB-dependent p38 activation under physiological conditions [30][31][32]. This suggests that the activation mechanisms of p38 may vary in different cells under various physiological or pathological conditions.…”

Section: Upstream Kinases That Activate P38mentioning

confidence: 99%

Activation and signaling of the p38 MAP kinase pathway

2005

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The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

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Regulation of the Maintenance of Peripheral T-Cell Anergy by TAB1-Mediated p38α Activation

Abstract: In anergic T cells, T-cell receptor (TCR)-These results imply that TAB1-mediated activation of p38␣ in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.

Cited by 41 publications

References 49 publications

Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

Activation and signaling of the p38 MAP kinase pathway

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Regulation of the Maintenance of Peripheral T-Cell Anergy by TAB1-Mediated p38α Activation

Abstract: In anergic T cells, T-cell receptor (TCR)-These results imply that TAB1-mediated activation of p38␣ in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.

Cited by 41 publications

References 49 publications

Targeted inhibition of IL‐10‐secreting CD25− Treg via p38 MAPK suppression in cancer immunotherapy

Targeted inhibition of IL‐10‐secreting CD25− Treg via p38 MAPK suppression in cancer immunotherapy

High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia

Activation and signaling of the p38 MAP kinase pathway

Contact Info

Product

Resources

About

Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy

Targeted inhibition of IL‐10‐secreting CD25⁻ Treg via p38 MAPK suppression in cancer immunotherapy