Functional roles of Cot/Tpl2 in mast cell responses to lipopolysaccharide and FcεRI-clustering.
Cot/Tpl2, a member of MAP kinase kinase kinase (MAPKKK), is indispensable for the ERK activation, as well as the production of TNF-α, IL-1β, IL-23, and PGE(2) in lipopolysaccharide (LPS)-stimulated macrophages. However, the expression and the functional roles of Cot/Tpl2 in mast cells have not been elucidated. The administration of LPS impairs allergic airway inflammation in a mast cell-dependent manner, and LPS stimulates mast cells to produce not only pro-inflammatory cytokines, such as IL-6 and TNF-α, but also Th2-type cytokines, such as IL-5, IL-10 and IL-13. Here, we examine the role of Cot/Tpl2 by using bone marrow-derived mast cells (BMMCs) from cot/tpl2 gene-deficient mice. Phosphorylation of ERKs was significantly decreased, whereas that of JNKs and p38 kinase was normal in LPS-stimulated cot/tpl2(-/-) BMMCs compared with wild-type counterparts. LPS-induced mRNA increase was significantly impaired for IL-5, IL-10, IL-13, and TNF-α, but was normal for IL-6, in cot/tpl2(-/-) BMMCs. On the other hand, degranulation by FcεRI-clustering from cot/tpl2(-/-) BMMCs was significantly enhanced compared with the WT control. Although the phosphorylation of ERKs and p38 kinase by FcεRI-clustering was similar in WT and cot/tpl2(-/-) BMMCs, the phosphorylation of Syk was significantly enhanced in cot/tpl2(-/-) BMMCs, which seemed to be due to the increased protein concentration of Syk. These results imply the functional importance of Cot/Tpl2 in mast cells during the course of allergic diseases such as asthma.
Chiba
Norika
N
Division of Biochemistry and Molecular Dentistry, Department of Developmental Medicine, Kagoshima University, Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
Kakimoto
Kyoko
K
Masuda
Akio
A
Matsuguchi
Tetsuya
T
D000818:Animals; D001249:Asthma / Q000276:immunology*; D005260:Female; D016753:Interleukin-10 / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics; D015848:Interleukin-5 / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017455:Receptors, IgE / Q000378:metabolism*
D018793:Interleukin-13; D015848:Interleukin-5; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D017455:Receptors, IgE; D016753:Interleukin-10; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse