TNF–· and IL–5 Gene Induction in IgE plus Antigen–Stimulated Mast Cells Require Common and Distinct Signaling Pathways

Abstract

Background: Mast cells produce a variety of cytokines and chemokines in a timely and tightly controlled fashion if stimulated via the FcεRI. Evidence is accumulating that the transcriptional induction of the corresponding genes and the release of these mediators are dependent on common and mediator–specific components of the signal transduction and transcription factor machinery. Methods: We addressed this issue by comparing the effects of mitogen activated protein (MAP) kinase pathway inhibitors and protein kinase C (PKC) inhibitors on the induction of TNF–α and IL–5 after IgE plus antigen (Ag) stimulation in CPII mouse mast cells using Western blot analyses and transient transfections of reporter gene plasmids. Results: TNF–α shows a strict dependence on the MAP kinase pathway, while IL–5 is either activated by PMA–dependent PKCs or along the MAP kinase pathway. In addition, both mediators are sensitive to PKCμ inhibition, suggesting involvement of this atypical, non–PMA dependent PKC in the overall induction process. Conclusion: While the two cytokines were recently shown to be regulated by a member of the nuclear factor of activated T–cells (NF–AT) transcription factor family, activator protein 1 (AP1) was identified as a cofactor at the TNF–α promoter while a GATA family member comprised the cofactor at the IL–5 promoter. This suggests that the differences in requirement for signal transduction cascades are the result of a different usage of NF–AT cofactors for transcription of each cytokine in mast cells.

α-Melanocyte Stimulating Hormone Acts as a Selective Inducer of Secretory Functions in Human Mast Cells

“…In agreement with our data, NF-AT-like transcription factors have been identified in the past in human and mouse mast cells (15). These molecules were shown to be involved in the anti-IgE-and PMA-induced transcriptional activation of various cytokine genes (15).…”

The Immunoglobulin E-Toll-Like Receptor Network

“…Additionally, activator protein 1 as mitogen-activated protein kinase pathways are involved [1, 12]. Together, these mechanisms induce the subsequent release and exocytosis of histamine and other preformed mediators of allergic inflammation by effector cells [13].…”

“…In this context, it is worth noting that several potential molecular intersection points between FcεRI and TLRs exist, such as the activation of the mitogen-activated protein kinase pathway or NF-ĸB signaling and others (fig. 1) [1, 12]. …”

Th2 Cytokine Production from Mast Cells Is Directly Induced by Lipopolysaccharide and Distinctly Regulated by c-Jun N-Terminal Kinase and p38 Pathways

“…Thus, the mechanisms of IL-5 mRNA translation and production remain largely unknown. There are several reports that show that IL-5 mRNA induction and protein production are dependent on the protein kinase C (PKC) pathway (69,70). Because LPS activates PKC in various cell types including mast cells (71)(72)(73)(74) and some PKC isoforms activate p38 kinases (75), IL-5 production may be regulated by sequential activation of PKC-p38 kinase.…”