Journal
BIOCHEMICAL JOURNAL
Volume 423, Issue -, Pages 71-78Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20090208
Keywords
inhibitory kappa B kinase beta (IKK beta); interleukin-1 (IL-1); nuclear factor kappa B (NF-kappa B); protein phosphatase 2C eta-2 (PP2C eta-2); protein phosphatase magnesium- or manganese-dependent; 1M (PPM1M)
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20013003]
- Grants-in-Aid for Scientific Research [21247031, 20013003] Funding Source: KAKEN
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IL-1 (interleukin-1) is a pro-inflammatory cytokine that has a variety of effects during the process of inflammation. Stimulating cells with IL-1 initiates a signalling cascade that includes the activation of NF-kappa B (nuclear factor kappa B), and subsequently induces a variety of inflammatory genes. Although the molecular mechanism for the IL-1-induced activation of N-F-kappa B has been well documented, much less is known about the mechanism by which protein phosphatases down-regulate this pathway. Here we show that mouse PP2C eta-2 (protein serine/threonine phosphatase 2C eta-2), a novel member of the protein serine/threonine phosphatase 2C family, inhibits the IL-1-NF-kappa B signalling pathway. Ectopic expression of PP2C eta-2 in human embryonic kidney HEK293IL-1RI cells inhibited the IL-1-induced activation of NF-kappa B. TAK1 (transforming-growth-factor-beta-activated kinase 1) mediates the IL-1 signalling pathway to NT7-kappa B, and we observed that the TAK1-induced activation of NF-kappa B was suppressed by PP2C eta-2 expression. Expression of IKK beta [I kappa B (inhibitory kappa B) kinase beta], which lies downstream of TAK1, activates NF-kappa B, and this activation was also readily reversed by PP2C eta-2 co-expression. Additionally, PP2C eta-2 knockdown with small interfering RNA further stimulated the IL-1-enhanced phosphorylation of IKK beta and destabilization of I kappa B alpha in HeLa cells. PP2C eta-2 knockdown also increased the IL-1-induced expression of IL-6 mRNA. Furthermore, IKK beta was readily dephosphorylated by PP2C eta-2 in vitro. These results suggest that PP2C eta-2 inhibits the IL-1-NF-kappa B signalling pathway by selectively dephosphorylating IKK beta.
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