gastrin-releasing-peptide and Arthritis--Rheumatoid

Many studies have shown that modulation of cytokine function is effective in ameliorating symptoms of rheumatoid arthritis. Neuropeptides have recently been shown to have powerful effects on the production and release of cytokines and have also been shown to exert potent proinflammatory and anti-inflammatory effects in animal models of inflammatory diseases. An analysis of cytokine and neuropeptide content of synovial fluid from patients with rheumatoid arthritis has revealed a significant correlation between two neuropeptides, bombesin/gastrin-releasing peptide and substance P, and the proinflammatory cytokine interleukin-6 as well as the erythrocyte sedimentation rate. These findings provide further evidence for a role of neuropeptides and cytokines in the pathophysiology of rheumatoid arthritis, as well as suggesting additional approaches for the development of novel therapeutic interventions.

Topics: Animals; Arthritis, Rheumatoid; Cytokines; Gastrin-Releasing Peptide; Humans; Substance P

Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA.

Topics: Animals; Arthritis, Rheumatoid; Cell Movement; Cell Proliferation; Chromones; Fibroblasts; Gastrin-Releasing Peptide; Gene Expression Regulation; Humans; Mice; Morpholines; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Bombesin; Signal Transduction; Synoviocytes

We determined the effects of etanercept on the serum concentrations of neuropeptides in RA patients. In a total of 11 patients who had been injected with etanercept, the serum levels of substance P, calcitonin gene-related peptide (CGRP), and gastrin-releasing peptide (GRP) were analyzed. Average levels of serum substance P were significantly reduced from 1.53 to 0.62 ng/ml after the injection of etanercept. In the CGRP and GRP analyses, these average levels dropped from 1.57 and 0.51 ng/ml to 0.44 and 0.04 ng/ml, respectively. Etanercept appears to decrease substance P levels with an improvement in disease activities.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Calcitonin Gene-Related Peptide; Etanercept; Female; Gastrin-Releasing Peptide; Humans; Immunoglobulin G; Male; Middle Aged; Receptors, Tumor Necrosis Factor; Substance P; Tumor Necrosis Factor-alpha

We have previously shown that levels of the neuropeptides substance P (SP) and bombesin/gastrin-releasing peptide (BN/GRP) in blood and synovial fluid correlate with levels of pro-inflammatory cytokines in patients with rheumatoid arthritis (RA). It is well-established that SP is present in nerve endings in the synovium whilst the source of BN/GRP in human joints is completely unknown. Nor is it known whether GRP-receptors (GRP-R) are present in human synovial tissue. This study aimed to investigate the expression pattern of SP, BN/GRP and their receptors (NK-1R and GRP-R) in synovial tissue. Synovial tissue specimens from patients with RA or osteoarthritis (OA) were processed for immunohistochemistry, in situ hybridisation and ELISA. The results show the presence of BN/GRP, but not SP, in cells in the synovial tissue at both the protein and mRNA level. We did not find immunoreactive BN/GRP in nerve structures. NK-1R and GRP-R were also expressed at both protein and mRNA levels in cells associated with blood vessels and cells in the interstitial tissue. ELISA analyses revealed both SP and BN/GRP to be present in synovial tissue extracts and that synovial levels of SP were higher in RA patients than those with OA. Our results indicate that BN/GRP is produced by non-neuronal cells in the synovial tissue. Furthermore, both BN/GRP and SP may exert their effects on the synovial tissue through the respective receptors. These results suggest that BN/GRP and SP may modulate inflammation and vascular events, and possibly healing processes in the synovium. Finally, nerves should not be considered as the source of BN/GRP in synovial tissue although this peptide is presumably intimately involved functionally in synovial tissue, a previously unrecognised fact.

Topics: Adult; Aged; Arthritis, Rheumatoid; Bombesin; Enzyme-Linked Immunosorbent Assay; Gastrin-Releasing Peptide; Humans; Immunohistochemistry; In Situ Hybridization; Knee Joint; Middle Aged; Osteoarthritis, Knee; Receptors, Neurokinin-1; RNA, Messenger; Staining and Labeling; Substance P; Synovial Membrane

It is well known that cytokines are highly involved in the disease process of rheumatoid arthritis (RA). Recently, targeting of neuropeptides has been suggested to have potential therapeutic effects in RA. The aim of this study was to investigate possible interrelations between five neuropeptides (bombesin/gastrin-releasing peptide (BN/GRP), substance P (SP), vasoactive intestinal peptide, calcitonin-gene-related peptide, and neuropeptide Y) and the three cytokines tumour necrosis factor (TNF)-alpha, IL-6, and monocyte chemoattractant protein-1 in synovial fluid of patients with RA. We also investigated possible interrelations between these neuropeptides and soluble TNF receptor 1 in serum from RA patients. Synovial fluid and sera were collected and assayed with ELISA or RIA. The most interesting findings were correlations between BN/GRP and SP and the cytokines. Thus, in synovial fluid, the concentrations of BN/GRP and SP grouped together with IL-6, and SP also grouped together with TNF-alpha and monocyte chemoattractant protein-1. BN/GRP and SP concentrations in synovial fluid also grouped together with the erythrocyte sedimentation rate. In the sera, BN/GRP concentrations and soluble TNF receptor 1 concentrations were correlated. These results are of interest because blocking of SP effects has long been discussed in relation to RA treatment and because BN/GRP is known to have trophic and growth-promoting effects and to play a role in inflammation and wound healing. Furthermore, the observations strengthen a suggestion that combination treatment with agents interfering with neuropeptides and cytokines would be efficacious in the treatment of RA. In conclusion, BN/GRP and SP are involved together with cytokines in the neuroimmunomodulation that occurs in the arthritic joint.

Topics: Adult; Arthritis, Rheumatoid; Cytokines; Female; Gastrin-Releasing Peptide; Humans; Male; Middle Aged; Neuroimmunomodulation; Substance P; Synovial Fluid

Gastrin-releasing peptide has a prominent role as a tumour marker in the diagnosis of small-cell lung carcinoma. This study was designed to assess the validity of a newly developed enzyme-linked immunosorbent assay (ELISA) for pro-gastrin-releasing peptide in patients with renal and systemic diseases.. Pro-gastrin-releasing peptide concentrations in sera from normal subjects and patients with small-cell lung carcinoma, diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, chronic glomerulonephritis, or undialysed or dialysed chronic renal failure were measured with the TND-4 Kit, a newly developed ELISA for pro-gastrin-releasing peptide.. All of the patients with normal renal function, whether they had diabetes mellitus (n=16), rheumatoid arthritis (n=10), systemic lupus erythematosus (n=12) or chronic glomerulonephritis (n=14), had serum pro-gastrin-releasing peptide concentrations less than 46 ng/l, the upper limit in normal subjects. In contrast, 14 or 16 patients (88%) with small-cell lung carcinoma, who had normal renal function, and 25 of 26 (96%) patients with chronic renal failure on haemodialysis had serum pro-gastrin-releasing peptide concentrations greater than 46 ng/l. The highest serum pro-gastrin-releasing peptide levels in patients with chronic renal failure, before and after initiating haemodialysis were 183 and 290 ng/l respectively. Ten of 16 (63%) small-cell lung carcinoma patients had serum pro-gastrin-releasing peptide concentrations greater than 290 ng/l, the highest level in haemodialysed patients. Serum pro-gastrin-releasing peptide concentrations were also elevated in patients with chronic glomerulonephritis or diabetes mellitus when their serum creatinine concentrations were greater than 120 micromol/l. And, there was a significant correlation, y=23.5+0.15x(n=22, r=0.82, P<0.001),between serum pro-gastrin-releasing peptide (y, in ng/l) and serum creatine (x in micromol/l) concentrations in those patients with renal dysfunction. The correlation between serum pro-gastrin-releasing peptide and serum urea nitrogen concentrations was likewise significant.. The evaluation of patients as to their renal functional state may be mandatory when serum pro-gastrin-releasing peptide levels are to be applied as one of the diagnostic tools for small-cell lung carcinoma or as a marker monitoring their clinical course.

Topics: Adult; Arthritis, Rheumatoid; Biomarkers, Tumor; Carcinoma, Small Cell; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Female; Gastrin-Releasing Peptide; Glomerulonephritis; Humans; Kidney Diseases; Kidney Failure, Chronic; Lung Neoplasms; Lupus Erythematosus, Systemic; Male; Middle Aged; Peptides; Protein Precursors; Reference Values; Reproducibility of Results