The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3

Natalia Ronkina; Nelli Shushakova; Christopher Tiedje; Tatiana Yakovleva; Maxim A.X. Tollenaere; Aaron Scott; Tanveer Singh Batth; Jesper Velgaard Olsen; Alexandra Helmke; Simon Holst Bekker-Jensen; Andrew R. Clark; Alexey Kotlyarov; Matthias Gaestel

doi:10.4049/jimmunol.1801221

The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3

Natalia Ronkina, Nelli Shushakova, Christopher Tiedje, Tatiana Yakovleva, Maxim A.X. Tollenaere, Aaron Scott, Tanveer Singh Batth, Jesper Velgaard Olsen, Alexandra Helmke, Simon Holst Bekker-Jensen, Andrew R. Clark, Alexey Kotlyarov, Matthias Gaestel

Molecular Aging Program

11 Citations (Scopus)

Abstract

Tristetraprolin (TTP) is an RNA-binding protein and an essential factor of posttranscriptional repression of cytokine biosynthesis in macrophages. Its activity is temporally inhibited by LPS-induced p38MAPK/MAPKAPK2/3-mediated phosphorylation, leading to a rapid increase in cytokine expression. We compared TTP expression and cytokine production in mouse bone marrow-derived macrophages of different genotypes: wild type, MAPKAP kinase 2 (MK2) deletion (MK2 knockout [KO]), MK2/3 double deletion (MK2/3 double KO [DKO]), TTP-S52A-S178A (TTPaa) knock-in, as well as combined MK2 KO/TTPaa and MK2/3 DKO/TTPaa. The comparisons reveal that MK2/3 are the only LPS-induced kinases for S52 and S178 of TTP and the role of MK2 and MK3 in the regulation of TNF biosynthesis is not restricted to phosphorylation of TTP at S52/S178 but includes independent processes, which could involve other TTP phosphorylations (such as S316) or other substrates of MK2/3 or p38MAPK Furthermore, we found differences in the dependence of various cytokines on the cooperation between MK2/3 deletion and TTP mutation ex vivo. In the cecal ligation and puncture model of systemic inflammation, a dramatic decrease of cytokine production in MK2/3 DKO, TTPaa, and DKO/TTPaa mice compared with wild-type animals is observed, thus confirming the role of the MK2/3/TTP signaling axis in cytokine production also in vivo. These findings improve our understanding of this signaling axis and could be of future relevance in the treatment of inflammation.

Original language	English
Journal	Journal of immunology (Baltimore, Md. : 1950)
Volume	203
Issue number	8
Pages (from-to)	2291-2300
Number of pages	10
ISSN	0022-1767
DOIs	https://doi.org/10.4049/jimmunol.1801221
Publication status	Published - 2019

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Ronkina, N., Shushakova, N., Tiedje, C., Yakovleva, T., Tollenaere, M. A. X., Scott, A., Batth, T. S., Olsen, J. V., Helmke, A., Bekker-Jensen, S. H., Clark, A. R., Kotlyarov, A., & Gaestel, M. (2019). The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3. Journal of immunology (Baltimore, Md. : 1950), 203(8), 2291-2300. https://doi.org/10.4049/jimmunol.1801221

Ronkina, N, Shushakova, N, Tiedje, C, Yakovleva, T, Tollenaere, MAX, Scott, A, Batth, TS , Olsen, JV, Helmke, A, Bekker-Jensen, SH, Clark, AR, Kotlyarov, A & Gaestel, M 2019, 'The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3', Journal of immunology (Baltimore, Md. : 1950), vol. 203, no. 8, pp. 2291-2300. https://doi.org/10.4049/jimmunol.1801221

@article{50b32132395d4f1e84302e40f9ef89da,

title = "The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3",

abstract = "Tristetraprolin (TTP) is an RNA-binding protein and an essential factor of posttranscriptional repression of cytokine biosynthesis in macrophages. Its activity is temporally inhibited by LPS-induced p38MAPK/MAPKAPK2/3-mediated phosphorylation, leading to a rapid increase in cytokine expression. We compared TTP expression and cytokine production in mouse bone marrow-derived macrophages of different genotypes: wild type, MAPKAP kinase 2 (MK2) deletion (MK2 knockout [KO]), MK2/3 double deletion (MK2/3 double KO [DKO]), TTP-S52A-S178A (TTPaa) knock-in, as well as combined MK2 KO/TTPaa and MK2/3 DKO/TTPaa. The comparisons reveal that MK2/3 are the only LPS-induced kinases for S52 and S178 of TTP and the role of MK2 and MK3 in the regulation of TNF biosynthesis is not restricted to phosphorylation of TTP at S52/S178 but includes independent processes, which could involve other TTP phosphorylations (such as S316) or other substrates of MK2/3 or p38MAPK Furthermore, we found differences in the dependence of various cytokines on the cooperation between MK2/3 deletion and TTP mutation ex vivo. In the cecal ligation and puncture model of systemic inflammation, a dramatic decrease of cytokine production in MK2/3 DKO, TTPaa, and DKO/TTPaa mice compared with wild-type animals is observed, thus confirming the role of the MK2/3/TTP signaling axis in cytokine production also in vivo. These findings improve our understanding of this signaling axis and could be of future relevance in the treatment of inflammation.",

author = "Natalia Ronkina and Nelli Shushakova and Christopher Tiedje and Tatiana Yakovleva and Tollenaere, {Maxim A.X.} and Aaron Scott and Batth, {Tanveer Singh} and Olsen, {Jesper Velgaard} and Alexandra Helmke and Bekker-Jensen, {Simon Holst} and Clark, {Andrew R.} and Alexey Kotlyarov and Matthias Gaestel",

year = "2019",

doi = "10.4049/jimmunol.1801221",

language = "English",

volume = "203",

pages = "2291--2300",

journal = "Journal of immunology (Baltimore, Md. : 1950)",

issn = "0022-1767",

publisher = "American Association of Immunologists",

number = "8",

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TY - JOUR

T1 - The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3

AU - Ronkina, Natalia

AU - Shushakova, Nelli

AU - Tiedje, Christopher

AU - Yakovleva, Tatiana

AU - Tollenaere, Maxim A.X.

AU - Scott, Aaron

AU - Batth, Tanveer Singh

AU - Olsen, Jesper Velgaard

AU - Helmke, Alexandra

AU - Bekker-Jensen, Simon Holst

AU - Clark, Andrew R.

AU - Kotlyarov, Alexey

AU - Gaestel, Matthias

PY - 2019

Y1 - 2019

N2 - Tristetraprolin (TTP) is an RNA-binding protein and an essential factor of posttranscriptional repression of cytokine biosynthesis in macrophages. Its activity is temporally inhibited by LPS-induced p38MAPK/MAPKAPK2/3-mediated phosphorylation, leading to a rapid increase in cytokine expression. We compared TTP expression and cytokine production in mouse bone marrow-derived macrophages of different genotypes: wild type, MAPKAP kinase 2 (MK2) deletion (MK2 knockout [KO]), MK2/3 double deletion (MK2/3 double KO [DKO]), TTP-S52A-S178A (TTPaa) knock-in, as well as combined MK2 KO/TTPaa and MK2/3 DKO/TTPaa. The comparisons reveal that MK2/3 are the only LPS-induced kinases for S52 and S178 of TTP and the role of MK2 and MK3 in the regulation of TNF biosynthesis is not restricted to phosphorylation of TTP at S52/S178 but includes independent processes, which could involve other TTP phosphorylations (such as S316) or other substrates of MK2/3 or p38MAPK Furthermore, we found differences in the dependence of various cytokines on the cooperation between MK2/3 deletion and TTP mutation ex vivo. In the cecal ligation and puncture model of systemic inflammation, a dramatic decrease of cytokine production in MK2/3 DKO, TTPaa, and DKO/TTPaa mice compared with wild-type animals is observed, thus confirming the role of the MK2/3/TTP signaling axis in cytokine production also in vivo. These findings improve our understanding of this signaling axis and could be of future relevance in the treatment of inflammation.

AB - Tristetraprolin (TTP) is an RNA-binding protein and an essential factor of posttranscriptional repression of cytokine biosynthesis in macrophages. Its activity is temporally inhibited by LPS-induced p38MAPK/MAPKAPK2/3-mediated phosphorylation, leading to a rapid increase in cytokine expression. We compared TTP expression and cytokine production in mouse bone marrow-derived macrophages of different genotypes: wild type, MAPKAP kinase 2 (MK2) deletion (MK2 knockout [KO]), MK2/3 double deletion (MK2/3 double KO [DKO]), TTP-S52A-S178A (TTPaa) knock-in, as well as combined MK2 KO/TTPaa and MK2/3 DKO/TTPaa. The comparisons reveal that MK2/3 are the only LPS-induced kinases for S52 and S178 of TTP and the role of MK2 and MK3 in the regulation of TNF biosynthesis is not restricted to phosphorylation of TTP at S52/S178 but includes independent processes, which could involve other TTP phosphorylations (such as S316) or other substrates of MK2/3 or p38MAPK Furthermore, we found differences in the dependence of various cytokines on the cooperation between MK2/3 deletion and TTP mutation ex vivo. In the cecal ligation and puncture model of systemic inflammation, a dramatic decrease of cytokine production in MK2/3 DKO, TTPaa, and DKO/TTPaa mice compared with wild-type animals is observed, thus confirming the role of the MK2/3/TTP signaling axis in cytokine production also in vivo. These findings improve our understanding of this signaling axis and could be of future relevance in the treatment of inflammation.

U2 - 10.4049/jimmunol.1801221

DO - 10.4049/jimmunol.1801221

M3 - Journal article

C2 - 31527197

AN - SCOPUS:85072994788

SN - 0022-1767

VL - 203

SP - 2291

EP - 2300

JO - Journal of immunology (Baltimore, Md. : 1950)

JF - Journal of immunology (Baltimore, Md. : 1950)

IS - 8

ER -

The Role of TTP Phosphorylation in the Regulation of Inflammatory Cytokine Production by MK2/3

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