title: MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages.
abstract: The mitogen activated protein kinases ERK1/2 play an important role in response to toll like receptor (TLR) activation and cytokine production, including IL-10 and IL-12. Here, we examined the role of MEK1 in ERK1/2 activation in response to TLR4 agonist by using bone marrow-derived macrophages (BMDMs) from wild type (WT) and Mek1(d/d)Sox2(Cre) mice. Our data demonstrates that MEK1 is essential for ERK1/2 activation in response to LPS. Furthermore, stimulation of the TLR4 receptor of BMDMs derived from Mek1(d/d)Sox2(Cre) mice showed enhanced STAT4 phosphorylation and increased IL-12 secretion, but exhibited a significantly lower IL-10 production as compared to WT macrophages. Most interestingly, TLR ligation in the presence of recombinant IL-10 (rIL-10) or retinoic acid (RA) led to ERK1/2 activation independent of MEK1 in BMDMs derived from Mek1(d/d)Sox2(Cre) mice and led to inhibition of STAT4 and decreased IL-12 levels. Collectively, these data suggest that MEK1 is required for TLR4 mediated ERK activation and in turn regulates the production of IL-10 and IL-12. It also indicates that ERK1/2 can be activated independent of MEK1 in the presence of IL-10 and RA and this activation negatively regulates IL-12, but positively regulates IL-10 production. These findings may have significant implications for the development of drugs that modulate MEK1 activity in the treatment of inflammatory, autoimmune and proliferative diseases such as cancer.
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Bouhamdan
authors.affiliation: Department of Pediatrics, Division of Critical Care, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI 48201, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Bauerfeld
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Talreja
authors.affiliation: Centre de Recherche sur le Cancer de l'Université Laval, CRCHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Beuret
authors.affiliation: Centre de Recherche sur le Cancer de l'Université Laval, CRCHU de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: lsamavat@med.wayne.edu.
authors.forename: Lobelia
authors.initials: L
authors.lastname: Samavati
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D057507:Mice, 129 Strain; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050797:STAT4 Transcription Factor / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D018664:Interleukin-12; D014212:Tretinoin; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse
keywords: ERK; IL-10; IL-12; MEK1; MEK2; Macrophages; STAT/JAK