The role of TTP phosphorylation in the regulation of inflammatory cytokine production by MK2/3

Research output: Contribution to journalArticlepeer-review

Authors

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

Colleges, School and Institutes

External organisations

  • University of Birmingham

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.

Details

Original languageEnglish
Pages (from-to)2291-2300
Number of pages10
JournalJournal of Immunology
Volume203
Issue number8
Publication statusPublished - 15 Oct 2019