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Cot/Tpl2 regulates IL-23 p19 expression in LPS-stimulated macrophages through ERK activation

K Kakimoto1, T Musikacharoen, N Chiba

  • 1Department of Oral Biochemistry, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.

Journal of Physiology and Biochemistry
|April 21, 2010
PubMed

Insights

Cot/Tpl2 kinase negatively regulates Th1 immunity but positively regulates Th17 immunity by controlling IL-23 expression in macrophages via the ERK pathway.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • The serine/threonine protein kinase Cot/Tpl2 is a known negative regulator of T-helper 1 (Th1) immunity.
  • Cot/Tpl2 inhibits interleukin-12 (IL-12) expression in antigen-presenting cells (APCs) stimulated by Toll-like receptor (TLR) ligands.

Purpose of the Study:

  • To investigate the role of Cot/Tpl2 in regulating T-helper 17 (Th17) type responses.
  • To elucidate the mechanism by which Cot/Tpl2 influences IL-23 production in macrophages.

Main Methods:

  • Comparison of IL-23 production in wild-type and Cot/Tpl2 knockout (Cot/Tpl2(-/-)) macrophages stimulated with lipopolysaccharide (LPS).
  • Analysis of IL-23 p19 mRNA induction levels.
  • Assessment of IL-23 expression following chemical inhibition of extracellular signal-regulated kinase (ERK) activity.

Main Results:

  • Cot/Tpl2(-/-) macrophages produced significantly less IL-23 in response to LPS compared to wild-type macrophages.
  • Decreased IL-23 production in Cot/Tpl2(-/-) macrophages was partly due to reduced IL-23 p19 mRNA induction.
  • Chemical inhibition of ERK activity mimicked the effect of Cot/Tpl2 deficiency on IL-23 expression.

Conclusions:

  • Cot/Tpl2 positively regulates IL-23 expression, a key cytokine for Th17 responses, through the ERK activation pathway.
  • Cot/Tpl2 plays a role in balancing Th1 and Th17 differentiation by modulating the IL-12/IL-23 expression ratio in APCs.

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