Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3(Mkk3)-deficient mice (original) (raw)
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2008
The expression of many inducible genes involved in cell growth and differentiation is regulated mainly by mitogen-activated protein kinases (MAPK)-signalling pathways. In this study we examined how JNK(SP600125) and p38(SB202190) MAPKs inhibitors influenced the inducible IL-12p40, IL-12p70 and IL-23 production. The quantity determination of these cytokines was performed by ELISA in culture supernatants. The inhibition of both JNK and p38 increased IL-12p40 production induced by all stimuli. The inhibition of p38MAPK down-regulated IL-23 production and up-regulated IL-12p40/p70 production in stimulated cells. We suggest the benefit of p38 control in the treatment of inflammatory and/or autoimmune diseases.
The expression of many inducible genes involved in cell growth and differentiation is regulated mainly by mitogen-activated protein kinases (MAPK)-signalling pathways. In this study we examined how JNK(SP600125) and p38(SB202190) MAPKs inhibitors influenced the inducible IL-12p40, IL- 12p70 and IL-23 production. The quantity determination of these cytokines was performed by ELISA in culture supernatants. The inhibition of both JNK and p38 increased IL-12p40 production induced by all stimuli. The inhibition of p38MAPK down-regulated IL-23 production and up-regulated IL- 12p40/p70 production in stimulated cells. We suggest the benefit of p38 control in the treatment of inflammatory and/or autoimmune diseases.
European Journal of Immunology, 2001
The p38 mitogen-activated protein kinases (p38 MAPK) are activated in lymphocytes and acessory cells during innate and antigen-specific responses. We show that an inhibitor of two isoforms of p38 MAPK, SB 203580, inhibited the antigen-initiated production of IL-12, and IFN-+ by cultures of splenic APC and naive CD4 + T cells. Paradoxically, SB 203580 enhanced the LPS plus IFN-+-initiated production of IL-12 by peritoneal exudate macrophages, and the LPS-initiated of the production of both IL-12 and IFN-+ by non-T non-B (scid) splenocytes. The enhancing effect of SB 203580 on the production of IL-12 by peritoneal exudate macrophages stimulated by LPS and IFN-+ was dose dependent (EC 50 0.3 ? M), was only seen at lower concentrations of IFN-+ and was due, at least in part, to a dosedependent (IC 50 0.3 ? M) inhibition of the production of IL-10. These results indicate first, that p38 MAP kinase activity is required for the production of IL-10, as well as that of proinflammatory cytokines such as IL-12 and IFN-+ , and, second, that the net effects of SB 203580 on the production of IL-12 and IFN-+ can be positive or negative, depending on stimuli, cell populations, and levels of cytokines such as IFN-+ and IL-10.
Journal of Biological Chemistry, 1999
We have shown recently that interleukin (IL)-2 activates the mitogen-activated protein (MAP) kinase family members p38 (HOG1/stress-activated protein kinase II) and p54 (c-Jun N-terminal kinase/stress-activated protein kinase I). Furthermore, the p38 MAP kinase inhibitor SB203580 inhibited IL-2-driven T cell proliferation, suggesting that p38 MAP kinase might be involved in mediating proliferative signals. In this study, using transfected BA/F3 cell lines, it is shown that both the acidic domain and the membrane-proximal serine-rich region of the IL-2R chain are required for p38 and p54 MAP kinase activation and that, as for p42/44 MAP kinase, this activation requires the Tyr 338 residue of the acidic domain, the binding site for Shc. It is well established that the acidic domain of the IL-2R chain is dispensable for IL-2-driven proliferation, and thus our observations suggest that neither p38 nor p54 MAP kinase activation is required for IL-2-driven proliferation of BA/F3 cells. In addition, the tetravalent guanylhydrazone inhibitor of proinflammatory cytokine production, CNI-1493, can block the activation of p54 and p38 MAP kinases by IL-2 but has no effect on IL-2-driven proliferation of BA/F3 cells, activated primary T cells, or a cytotoxic T cell line. Furthermore, our observations provide evidence for the existence of an additional, unknown target of the p38 MAP kinase inhibitor SB203580, the activation of which is essential for mitogenic signaling by IL-2.
Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice
International Journal of Molecular Sciences, 2021
Mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) are members of the MAP2K family that can activate downstream mitogen-activated protein kinases (MAPKs). MKK4 has been implicated in the activation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, while MKK7 has been reported to activate only JNK in response to different stimuli. The stimuli, as well as the cell type determine which MAP2K member will mediate a given response. In various cell types, MKK7 contributes to the activation of downstream MAPKs, JNK, which is known to regulate essential cellular processes, such as cell death, differentiation, stress response, and cytokine secretion. Previous studies have also implicated the role of MKK7 in stress signaling pathways and cytokine production. However, little is known about the degree to which MKK4 and MKK7 contribute to innate immune responses in macrophages or during inflammation in vivo. To address this question and to elucidate the role of MKK4 and MKK7 in m...
Journal of Biological Chemistry, 2002
STAT6 functions as a critical mediator of IL-4-stimulated gene activation, and the function of STAT6 is regulated by both tyrosine and serine kinase activities. Here we analyzed the role of serine phosphorylation in regulation of STAT6-mediated transcription. Optimal transcriptional response of IL-4-inducible promoters requires costimulatory signals through CD40-stimulated intracellular kinases such as p38 MAPK. We found that the p38 MAPK inhibitor SB202190 as well as the dominant negative p38 MAPK inhibited interleukin (IL)-4 regulated expression of CD23 in Ramos B cells. IL-4 stimulation did not stimulate p38 MAPK activity, but inhibition of p38 MAPK activity directly correlated with inhibition of IL-4-induced gene activation. Dissection of individual response elements on IL-4-regulated promoter showed that C/EBP-mediated transcription was insensitive to SB202190 treatment in B cells whereas STAT6-mediated transcription was regulated by p38 MAPK. The IL-4-induced immediate activation events of STAT6 were not affected by p38 MAPK activity. Furthermore, phosphoamino acid analysis and phosphopeptide mapping indicated that STAT6 is not a direct substrate for p38 MAPK. Instead, p38 MAPK was found to directly regulate the activity of the transactivation domain of STAT6. These results show that, in addition to the well established proinflammatory effects, p38 MAPK also provides a costimulatory signal for IL-4-induced gene responses by directly stimulating the transcriptional activation of STAT6.
The cellular response to treatment with proinflammatory cytokines or exposure to environmental stress is mediated, in part, by the p38 group of mitogen-activated protein (MAP) kinases. We report the molecular cloning of a novel isoform of p38 MAP kinase, p38 beta 2. This p38 MAP kinase, like p38 alpha, is inhibited by the pyridinyl imidazole drug SB203580. The p38 MAP kinase kinase MKK6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma MAP kinase isoforms, while MKK3 activates only p38 alpha and p38 gamma MAP kinase isoforms. The MKK3 and MKK6 signal transduction pathways are therefore coupled to distinct, but overlapping, groups of p38 MAP kinases.
Journal of Leukocyte Biology, 2006
The p38 mitogen-activated protein kinase regulates many cellular processes in almost all eukaryotic cell types. In T cells, p38 was shown to regulate thymic development and cytokine production. Here, the role of p38 on interleukin-2 (IL-2) production by human peripheral blood CD4 ؉ T cells was examined. When T cells were stimulated under weak stimulation conditions, pharmaceutical and molecular p38 inhibitors induced a dramatic increase of IL-2 production. In contrast, IL-2 levels were not affected significantly when strong stimulation was provided to T cells. The increase in IL-2 production, following p38 inhibition, was associated with a strong up-regulation of extracellular signal-regulated kinase (Erk)1/2 activity. Furthermore the Erk inhibitor U0126 was able to counteract the effect of p38 inhibition on IL-2 production, supporting the conclusion that p38 mediates its effect through Erk. These results suggest that the p38 kinase, through its ability to control Erk activation levels, acts as a gatekeeper, which prevents inappropriate IL-2 production. Also, the finding that p38 acts in a strength-ofstimulation-dependent way provides an explanation for previously reported, contradictory results regarding the role of this kinase in IL-2 expression.