| First Author | MacNeil AJ | Year | 2011 |
| Journal | J Immunol | Volume | 187 |
| Issue | 6 | Pages | 3374-82 |
| PubMed ID | 21841136 | Mgi Jnum | J:179249 |
| Mgi Id | MGI:5301503 | Doi | 10.4049/jimmunol.1003126 |
| Citation | MacNeil AJ, et al. (2011) MAPK kinase 3 specifically regulates Fc epsilonRI-mediated IL-4 production by mast cells. J Immunol 187(6):3374-82 |
| abstractText | Mast cells play a central role in allergic inflammation and are activated through cross-linking of FcepsilonRI receptor-bound IgE, initiating a signaling cascade resulting in production of biologically potent mediators. Signaling pathways in the regulation of specific mediators remain incompletely defined. In this study, we examined the role of MAPK kinase 3 (MKK3) in IgE-dependent mast cell activation. In an in vivo model of passive cutaneous anaphylaxis, MKK3-deficient mice showed a deficit in late-phase IgE-dependent inflammation. To characterize the mechanism of this deficiency, we cultured bone marrow-derived mast cells (BMMCs) from wild-type and MKK3-deficient mice. We found that FcepsilonRI-mediated mast cell activation induced rapid MKK3 phosphorylation by 5 min, diminishing slowly after 6 h. In MKK3-deficient BMMCs, phosphorylation of p38 was reduced at early and later time points. Among 40 cytokines tested using a protein array, IL-4 was the only cytokine specifically downregulated in MKK3-deficient BMMCs. Reduced IL-4 expression was seen in the local skin of MKK3-deficient mice following passive cutaneous allergic reaction. Furthermore, early growth response-1 (Egr1) bound to the promoter of IL-4 in FcepsilonRI-activated mast cells, and Egr1 transcription factor activity was diminished in MKK3-deficient BMMCs. Finally, mast cell-deficient mice reconstituted with MKK3-deficient BMMCs displayed a significantly impaired late-phase allergic inflammatory response. Thus, mast cell MKK3 signaling contributes to IgE-dependent allergic inflammation and is a specific regulator of FcepsilonRI-induced IL-4 production. |
