Protein kinase C alpha, betaI, and betaII isozymes regulate cytokine production in mast cells through MEKK2/ERK5-dependent and -independent pathways.
Regulation of MAPK pathways by PKC isoforms was examined in murine bone marrow-derived mast cells (BMMCs). The PKCalpha, betaI, and betaII isoforms showed the most robust activation after FcepsilonR1-mediated stimulation by anti-ovalbumin specific IgE and ovalbumin (IgE-ova). PKCalpha, betaI, and betaII were all involved in activation of JNK, MEKK2, and ERK5, with differential relative contributions of each isoform to specific MAPK pathway components. BMMCs from mice lacking MEKK2 showed reduced production (50-60%) of IL-6, IL-13, and TNF-alpha after stimulation, demonstrating MEKK2-dependent and -independent pathways for cytokine production. Cytokine production was stimulated by over-expression of PKC in cells from MEKK2-deficient and wild-type mice. Activation of ERK5 did not occur in BMMCs lacking MEKK2, indicating that MEKK2-independent cytokine production was also ERK5-independent. Since MAPK modules differentially regulate mast cell functions, including degranulation and cytokine production, it is suggested that specific functions could be targeted by inhibiting specific PKC isoforms.
Li
Guiming
G
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Lucas
Joseph J
JJ
Gelfand
Erwin W
EW
D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000276:immunology / Q000378:metabolism; D048730:MAP Kinase Kinase Kinase 2 / Q000276:immunology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017455:Receptors, IgE / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D017455:Receptors, IgE; D011493:Protein Kinase C; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; C482619:Map3k2 protein, mouse; D048670:MAP Kinase Kinase 4