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TPL2 meets p38MAPK: emergence of a novel positive feedback loop in inflammation

Manoj B Menon1, Matthias Gaestel1

  • 1Institute of Physiological Chemistry, Hannover Medical University, Carl-Neuberg-Str. 1, Hannover 30625, Germany.

The Biochemical Journal
|September 29, 2016
PubMed

Insights

Toll-like receptor signaling activates p38 mitogen-activated protein kinase (MAPK) for innate immunity. Researchers discovered TPL2 activates MKK3/6, a new pathway crucial for tumor necrosis factor-alpha (TNFα) biosynthesis and inflammation.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • p38 MAPK activation by Toll-like receptor signaling is vital for innate immunity and cytokine production.
  • Upstream activators of p38 MAPK include MAP2Ks (MKK3/6, MKK4) and MAP3Ks (e.g., TAK1).
  • TPL2 was previously considered exclusive to ERK1/2 activation via MKK1/2.

Purpose of the Study:

  • To identify novel substrates of TPL2 in macrophages.
  • To elucidate the role of TPL2 in Toll-like receptor-mediated inflammatory signaling.
  • To investigate the contribution of TPL2 to TNFα biosynthesis and associated signaling pathways.

Main Methods:

  • Screening for TPL2 substrates in lipopolysaccharide (LPS)-stimulated macrophages.
  • Utilizing catalytic-dead TPL2 (Map3k8(D270A/D270A)) knockin macrophages for functional studies.
  • Analysis of TNFα biosynthesis and TNF-receptor 1 signaling pathways.

Main Results:

  • TPL2 was identified as a novel activator of MKK3/6.
  • TPL2-mediated activation of MKK3/6 significantly contributes to LPS-induced TNFα biosynthesis.
  • This pathway is essential for TNF-receptor 1 signaling and involves a positive feedback loop with p38 MAPK.

Conclusions:

  • A new signaling pathway involving TAK1, IκB kinase, p105 NFκB, TPL2, MKK3/6, and p38 MAPK is established in macrophages.
  • TPL2 plays a critical role in innate immune inflammatory responses.
  • A positive feedback loop between p38 MAPK and TPL2 regulates inflammation.
Keywords:
Toll-like receptorsmitogen-activated protein kinasesstress kinasestumour necrosis factors

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