Aggregation of the FcεRI on Mast Cells Stimulates c-Jun Amino-terminal Kinase Activity

Abstract

Aggregation of the high-affinity Fc receptors for immunoglobulin E (IgE) (Fc⑀RI) on the surface of mast cells initiates intracellular signal transduction pathways including the tyrosine phosphorylation of cellular proteins, phosphoinositide hydrolysis, an increase in intracellular calcium, and protein kinase C activation. These signals are believed to be involved in the exocytic release of inflammatory mediators such as vasoactive amines, cytokines, and lipid metabolites. However, the downstream consequences of these early activation events are not well defined. One exception is the activation of the extracellular signal-regulated kinases/mitogen-activated protein kinases. One member of the mitogen-activated protein kinase superfamily, designated c-Jun amino-terminal kinase (JNK), has been recently identified. JNK is activated following dual phosphorylation at a Thr-Pro-Tyr motif in response to diverse stimuli including tumor necrosis factor-␣, heat shock, or ultraviolet irradiation. We found that JNK was strongly activated by antigen cross-linking in a mouse mast cell line passively sensitized with ovalbumin-specific IgE. Anti-mouse IgE antibody also activated JNK. MEK kinase 1 (MEKK1) which activates the JNK activator, JNK kinase (JNKK), was similarly activated by antigen stimulation. JNK but not p42 erk2 activation induced by antigen was significantly inhibited in the presence of wortmannin, a known inhibitor of phosphatidylinositol 3-kinase. These results indicate that in response to the aggregation of Fc⑀RI on mast cells, phosphatidylinositol 3-kinase activation is involved in the stimulation of the MEKK1, JNKK, JNK pathway.Mast cells play a central role in inflammatory and immediate allergic reactions. The multivalent binding of antigen to receptor-bound IgE and the subsequent aggregation of the highaffinity Fc receptors for IgE (Fc⑀RI) provide the trigger for activation of mast cells. Fc⑀RI aggregation results in the release of inflammatory mediators from secretory granules, which contain preformed mediators such as histamine, and the generation of leukotriene C4, prostaglandin D2, and a variety of cytokines (1-4). These mast cell responses are regulated by intracellular signal transduction pathways initiated by Fc⑀RI aggregation. The first demonstrable response to Fc⑀RI aggregation is tyrosine phosphorylation and activation of phospholipase C␥, which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate resulting in the liberation of inositol 1,4,5-trisphosphate and diacylglycerol (5). The elevation of diacylglycerol and the mobilization of Ca 2ϩ from intracellular and extracellular sources result in the activation of protein kinase C (6). In addition to the activation of phospholipase C␥ and protein kinase C, which appears to be essential for the Fc⑀RI-mediated release of preformed mediators (7), it was recently shown that the aggregation of Fc⑀RI on rat basophilic leukemia 2H3 (RBL-2H3) cells induces histamine and leukotriene release following activation of the phosphatidylinositol 3-kinase...

Rac and Phosphatidylinositol 3-Kinase Regulate the Protein Kinase B in FcεRI Signaling in RBL 2H3 Mast Cells

“…PI3-kinase activity also appears to be required for these signaling events (7,(53)(54)(55). Therefore, we studied the relationship among PI3-kinase, its effector PKB, and Rac in RBL cells by using various toxins as pharmacological tools.…”

Role of MEKK2-MEK5 in the regulation of TNF-α gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells

“…We have previously shown that ERK, p38, and JNK MAPK pathways are activated in MC͞9 cells in response to these mast cell stimuli (27,28). We have also shown that MEKK2 is required for OVA͞IgE, KL, and IL3 activation of JNK.…”

Redox regulation of mast cell histamine release in thioredoxin-1 (TRX) transgenic mice

“…FcεRI ligation results in the activation of mitogen-activated protein kinase (MAPK) pathways that include c-Jun N-terminal kinase (JNK) and p38 MAPK. JNK and p38 MAPK activate transcription factors that regulate the expression of cytokine genes such as IL-6 and TNF-α [28][29][30][31]. It is known that ROS activates the signaling pathways to NF-κB, which are suppressed by TRX overexpression through scavenging of ROS in cytosol.…”