Histamine and tryptase modulate asthmatic airway smooth muscle GM-CSF and RANTES release

Abstract

Degranulating mast cells are increased in the airway smooth muscle (ASM) of asthmatics, where they may influence ASM function. The aim of the present study was to determine whether histamine and tryptase modulate ASM cell granulocyte-macrophage colonystimulating factor (GM-CSF) and RANTES (regulated on activation, normal T-cell expressed and secreted) release and also to examine which receptors are involved in this release.Confluent, quiescent ASM cells from asthmatic and nonasthmatic donors were treated with histamine (1 mM-100 mM) with and without histamine receptor antagonist pre-treatment, or the protease-activated receptor (PAR)-2 agonists tryptase (0.5-5 nM) and SLIGKV (100 and 400 mM). The cells were then stimulated with interleukin (IL)-1b and/or tumour necrosis factor (TNF)-a (10 ng?mL -1 ) or left unstimulated for 24 h. Release of GM-CSF and RANTES was determined by ELISA and prostaglandin (PG)E 2 measured by enzyme immunoassay. Neither histamine nor tryptase induced ASM GM-CSF or RANTES secretion. However, histamine increased IL-1b-induced GM-CSF release and markedly reduced TNF-a-induced RANTES release by both asthmatic and nonasthmatic cells to a similar extent, but did not modulate PGE 2 release. All changes involved activation of the histamine H1 receptor as they were partially or fully blocked by chlorpheniramine, but not ranitidine. Tryptase, via its proteolytic activity, also potentiated GM-CSF, but not RANTES, release from asthmatic and nonasthmatic ASM cells induced by both cytokines. PAR-2 involvement in the tryptase potentiation was unlikely because SLIGKV had no effect.In conclusion, mast cells, through histamine and tryptase, may locally modulate airway smooth muscle-induced inflammation in asthma.

Bitter Taste Receptor Function in Asthmatic and Nonasthmatic Human Airway Smooth Muscle Cells

“…The asthmatic state has long been recognized as one that includes dysregulation of airway GPCRs, including those that act to contract and relax airway smooth muscle. Such alterations have been observed in vivo and ex vivo in human and animal airways and in cultured HASM cells (14)(15)(16)(17)(18)(19)(20). These findings include altered [Ca 21 ] signaling from G q -coupled receptors, such as M 3 -muscarinic and H1-histamine, and cAMP signaling from b 2 AR (14,17,18).…”

“…Even in passaged cultured HASM cells, without the addition of proinflammatory agents in the media, cells derived from patients with fatal asthma show distinct phenotypes compared with cells derived from donors without asthma. These include differences in receptor signaling, second messenger-dependent enzyme function, the response to viral infection, cell proliferation, and intracellular events, notably "distal" to early interaction genes (15,16,32). The breadth of documented changes in HASM phenotype from asthma or an inflammatory environment requires that potentially new therapeutic agents be tested in this context.…”

Mast cell regulation of airway smooth muscle function in asthma

“…Pharmacological blockade suggested that the effects of histamine were predominantly mediated via the H1 and not the H2 receptor. This was unexpected as CHHABRA et al [47] predicted that stimulation of H2 receptors would increase intracellular cyclic adenosine monophosphate and thus inhibit GM-CSF release, while at the same time potentiating RANTES release. The authors therefore proposed that the H1-mediated effects predominated and occur via activation of H1-coupled phospholipase C. However, it must be borne in mind that G-protein coupled receptors (GPCRs), such as H1 and H2, that were once thought to mediate all their effects via modulation of intracellular cyclic nucleotides are now known to couple to many diverse signalling pathways [48].…”

“…In the present issue of the European Respiratory Journal, CHHABRA et al [47] have examined the ability of two mast cell mediators, histamine and tryptase, to modify the synthetic ability of the ASM derived from both asthmatic and nonasthmatic subjects [47]. Specifically, they examined the release of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) and the RANTES (regulated on activation, normal T-cell expressed and secreted) chemokine.…”

Asthma and Mast Cell Biology

“…Therefore, mast cells participate in the development of allergic reactions through cross-linking of their surface high affinity receptors for IgE (FceRI) leading to degranulation and the release of vasoactive, proinflammatory compounds, such as metabolites, histamine, cytokines, proteolytic enzymes and arachidonic acid compounds. Human mast cell proteases increase C-C chemokine (CCL8) and fibronectin in cultured airway smooth muscle cells (41 ).…”