Tachykinin activation of human monocytes from patients with interstitial lung disease, healthy smokers or healthy volunteers

Abstract

Summary Three types of tachykinin receptors, NK 1 , NK 2 and NK 3 , have been described to preferentially interact with substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) respectively. Experimental evidence indicates that SP and NKA modulate the activity of inflammatory and immune cells, including mononuclear ones, and points to their involvement in lung pathophysiology. We previously reported that NK 1 and NK 2 receptors are present on monocytes (MO) isolated from healthy donors or rheumatoid patients -a greater sensitivity to NK 2 receptor stimulation was observed in the latter condition. This study evaluated the effects of SP and NKA, as well as NK 1 and NK 2 selective agonists and antagonists, on MO obtained from healthy volunteers, healthy smokers or patients with interstitial lung diseases (e.g. sarcoidosis and idiopathic pulmonary fibrosis). Superoxide anion (O 2 -) production was chosen as a parameter of cell activation. SP and NKA dose-dependently evoked O 2 -production from MO in all the conditions evaluated, their effects being competitively antagonized by selective antagonists (CP 96 345 and MEN 10 627, respectively). When selective NK 1 and NK 2 agonists were used, [Sar 9 Met(O 2 ) 11 ]SP, a selective NK 1 agonist, induced a more than doubled O 2 production in MO obtained from patients with interstitial lung diseases as compared to healthy volunteers, whereas MO isolated from healthy volunteers were more sensitive to NK 2 receptor stimulation.

Neurokinin A engages neurokinin-1 receptor to induce NF-κB-dependent gene expression in murine macrophages: implications of ERK1/2 and PI 3-kinase/Akt pathways

“…NKA, in addition to SP, is an important neuropeptide involved. In addition to earlier findings (9,15,29,30,50), our study, for the first time, shows that NKA stimulation of murine macrophages leads to activation of NF-B, a transcription factor that has a crucial modulatory role in inflammation, immunity, cell proliferation, and apoptosis (53). NF-B can be activated by three mechanisms: the classical pathway dependent on NF-B inhibitory protein IB degradation and two atypical pathways [one is through the processing of p100 and release of p52/RelB in the nucleus; the other is through the phosphorylation of p65 at multiple serine sites by some protein kinases (34,47)].…”

“…It induces histamine release from mast cells (15) and primes neutrophils for increased superoxide anion production in response to formyl-methionyl-leucyl-phenylalanine (50). It stimulates superoxide anion production and tumor necrosis factor-␣ (TNF-␣) mRNA expression from human monocytes (9,29) and also induces de novo protein synthesis and release of interleukin (IL)-1, TNF-␣, and IL-6 from human blood monocytes (30).…”

Cutaneous allergic contact dermatitis responses are diminished in mice deficient in neurokinin 1 receptors and augmented by neurokinin 2 receptor blockage

“…Although NKA has been demonstrated to induce superoxide anion production (51,52), to enhance T cell proliferation (53) or to promote neutrophil adherence (54), which would be in favor of a proinflammatory role of NKA, similar effects have also been reported for CGRP (55)(56)(57), and there is now considerable evidence that CGRP is a profound inhibitor of immediate and delayed-type hypersensitivity reactions (29,58). Noteworthy, NKA has also been demonstrated to induce nitric oxide (NO) synthase expression and NO release (59).…”

The role of substance P in inflammatory disease

“…Increased levels of SP have been found in BAL fluid recovered from patients with IPF and sarcoidosis, and SP activates monocytes recovered from BAL fluid more in patients with IPF and sarcoidosis than healthy volunteers (Takeyama et al, 1996; Brunelleschi et al, 2000). We recently demonstrated upregulated NK‐1R expression in BAL cells, bronchial epithelium, and granulomas of patients with sarcoidosis compared with normal controls (O'Connor et al, 2003).…”