TNF increases expression of IL-4 and PARs in mast cells

Department of Pathophysiology, Hainan Medical College, Haikou, Hainan.
Cellular Physiology and Biochemistry (Impact Factor: 2.88). 08/2010; 26(3):327-36. DOI: 10.1159/000320556
Source: PubMed


Tumor necrosis factor (TNF) is a proinflammatory cytokine which has been shown to be actively involved in the pathogenesis of allergic inflammation. However, little is known of the effects of TNF on cytokine secretion and protease activated receptor (PAR) expression in mast cells. In the present study, we examined potential influence of TNF on IL-4 and IL-12 release from P815 cells and PAR expression in P815 cells by using flow cytometry analysis, quantitative real time PCR, ELISA and cellular activation of signaling ELISA (CASE) techniques. The results showed that TNF induced up to 2.7-fold increase in IL-4, but not IL-12 release from P815 cells, and PAR-2 antagonist peptide FSLLRY-NH(2) and PAR-4 antagonist peptide trans-cinnamoyl (tc)-YPGKF-NH(2) did not affect TNF induced IL-4 release. Approximately up to 2.4 and 2.3 fold increases in expression of PAR-2 and PAR-4 were observed when cells were incubated with TNF. Pretreatment of cells with TNF for 60 min enhanced trypsin and tryptase induced PAR-2 expression by 2.4 and 2.3 fold; PAR-3 expression by 1.6 and 1.7 fold and PAR-4 expression by 1.6 and 1.7 fold, respectively. LY294002, an inhibitor PI3K abolished TNF induced IL-4 release and phosphorylation of Akt in P815 cells, indicating Akt cell signalling pathway is involved in the event. In conclusion, TNF can stimulate IL-4 release from mast cells through an Akt cell signalling pathway dependent, but PAR independent mechanism. TNF may serve as a regulator for IL-4 production and PAR expression, and through which participates in the mast cell related inflammation.

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    • "IL-33 induces mast cell secretion of IL-6, IL-13 and CCL2 which, in turn, modulates microglial cell activity. Mast cell tryptase cleaves and activates microglial cell proteinase-activated receptor 2 (leading to purinergic P2X 4 receptor up-regulation) [99], while IL-6 and TNF-α from microglia can up-regulate mast cell expression of proteinase-activated receptor 2, thereby activating mast cells and TNF-α release [100]. The complement system appears to participate in this bidirectional network, as well: the receptor for chemoattractant C5a is up-regulated on reactive astrocytes and microglia in inflamed CNS tissue [101]: Neuroinflammation causes C5a peptide release [102]; there is crosstalk between C5a and TLR4; C5a receptor is up-regulated in activated mast cells and is a strong mast cell chemoattractant signal towards C5a peptide. "
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    ABSTRACT: Cells of the immune system and the central nervous system are capable of interacting with each other. The former cell populations respond to infection, tissue injury and trauma by releasing substances capable of provoking an inflammatory reaction. Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders such as anxiety/depression and schizophrenia. Neuroinflammation may also raise the brain's sensitivity to stress, resulting in stress-related neuropsychiatric disorders, such as anxiety or depression. The cytokine network plays a large part in how immune system cells influence the central nervous system. Further, inflammation resulting from activation of innate immune system cells in the periphery can impact on central nervous system behaviors, such as depression and cognitive performance. In this review, we will present the reader with the current state of knowledge which implicates both microglia and mast cells, two of the principle innate immune cell populations, in neuroinflammation. Further, we shall make the case that dysregulation of microglia and mast cells may impact cognitive performance and, even more importantly, how their cell-cell interactions can work to not only promote but also amplify neuroinflammation. Finally, we will use this information to provide a starting point to propose therapeutic approaches based upon naturally-occurring lipid signaling molecules.
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    • "TNF also elevates PAR-2 expression on HMC-1 mast cells [23], and IL-12 upregulates PAR-4 expression on MC/9 mast cells [20]. Furthermore, tryptase-induced PAR-2 expression can be enhanced by IL-12 [20], TNF [31], RANTES [32], and IL-29 [29], and tryptase-induced PAR-3 and PAR-4 expression is upregulated by TNF on P815 mast cells [31]. It is also observed that trypsin-induced expression of PAR-1, -2, and -4 can be enhanced by RANTES [32] (Table 1). "
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    • "IL-4 production during antigen presentation to Th cells is critical for the development of Th2 cells50. Th2 cells31, mast cells51,52 and basophils53, and EC29 release substantial quantities of IL-4 and IL-13. "
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