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MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages

Mohamad Bouhamdan1, Christian Bauerfeld2, Jaya Talreja1

  • 1Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA.

Cellular Signalling
|July 26, 2015
PubMed

Insights

MEK1 is crucial for toll-like receptor 4 (TLR4) mediated ERK activation, regulating IL-10 and IL-12 cytokine production. ERK1/2 can activate independently of MEK1 under specific conditions, impacting inflammatory responses.

Area of Science:

  • Immunology
  • Cell Signaling
  • Molecular Biology

Background:

  • Mitogen-activated protein kinases (MAPKs), specifically ERK1/2, are key mediators in cellular responses.
  • Toll-like receptor (TLR) activation triggers signaling pathways involved in immune responses and cytokine production.
  • Interleukin-10 (IL-10) and Interleukin-12 (IL-12) are critical cytokines in regulating inflammation and immunity.

Purpose of the Study:

  • To investigate the role of MEK1 in ERK1/2 activation downstream of TLR4 signaling.
  • To elucidate the impact of MEK1 deficiency on cytokine production (IL-10 and IL-12) following TLR4 stimulation.
  • To explore alternative pathways for ERK1/2 activation independent of MEK1 in response to TLR ligation and specific signaling molecules.

Main Methods:

  • Utilized bone marrow-derived macrophages (BMDMs) from wild-type (WT) and Mek1(d/d)Sox2(Cre) mice.
  • Stimulated BMDMs with a TLR4 agonist (LPS).
  • Analyzed ERK1/2 activation, STAT4 phosphorylation, and cytokine (IL-10, IL-12) production.
  • Investigated TLR ligation in the presence of recombinant IL-10 (rIL-10) or retinoic acid (RA).

Main Results:

  • MEK1 is essential for ERK1/2 activation in response to LPS-induced TLR4 stimulation.
  • BMDMs lacking MEK1 exhibited enhanced STAT4 phosphorylation and increased IL-12 secretion, but reduced IL-10 production compared to WT.
  • TLR ligation with rIL-10 or RA induced MEK1-independent ERK1/2 activation, leading to inhibited STAT4 phosphorylation and decreased IL-12, while promoting IL-10 production.

Conclusions:

  • MEK1 is a critical regulator of TLR4-mediated ERK activation and subsequent IL-10 and IL-12 production.
  • ERK1/2 activation can occur independently of MEK1 under specific conditions (presence of IL-10/RA), modulating cytokine profiles.
  • These findings highlight MEK1 as a potential therapeutic target for inflammatory, autoimmune, and proliferative diseases.
Keywords:
ERKIL-10IL-12MEK1MEK2MacrophagesSTAT/JAK

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