Interleukin-18 induces serum amyloid A (SAA) protein production from rheumatoid synovial fibroblasts
Introduction
The serum amyloid A (SAA) isoforms protein are precursors of amyloid A (AA) protein, a major component of the fibrous deposits in amyloidosis associated with chronic inflammatory diseases such as rheumatoid arthritis (Steel and Whitehead, 1994). SAA is an acute phase reactant synthesized by the liver in response to inflammatory cytokines and secreted in the plasma (Uhlar and Whitehead, 1999). SAA protein gene family consists of 4 members, which are divided into two classes, acute phase and constitutive SAA (Sipe, 1999). Although acute phase SAA encoded by the two genes, SAA1 and SAA2, is induced by inflammatory stimuli up to 1000-fold, the constitutive SAA4 is only inducible to a small degree (Steel et al., 1993). There is a evidence suggesting that the human SAA3 is a pseudogene (Sellar and Whitehead, 1994). Like other acute phase proteins, SAA is synthesized in the liver, however, extrahepatic A-SAA synthesis has been confirmed, for example, in vascular smooth muscle cells and synovial cells Meek et al., 1994, Kumon et al., 1999. Furthermore, multiple functions such as chemotaxis and collagenase induction have been assigned to SAA Xu et al., 1995, Brinckerhoff et al., 1989. IL-18, a member of the IL-1 cytokine family, is also highly expressed in the RA synovium and is implicated in the pathogenesis of RA as a proinflammatory cytokine (Gracie et al., 1999). The present study was undertaken to assess whether IL-18 is associated with the synovial inflammation of RA. We examined the concentrations of IL-18 and SAA in synovial fluids from RA patients as well as in vitro effects of IL-18 on rheumatoid synovial cells.
Section snippets
Patients
Patients who presented to Nagasaki University Arthritis Clinics were included in the study. Synovial fluids were obtained from 24 patients with RA diagnosed according to the 1987 revised criteria American Rheumatism Association and 13 patients with osteoarthritis (OA). Synovial fluids were removed for therapeutic purpose. The synovial fluids obtained from the study subjects were collected and stored at −20 °C.
Reagents
Recombinant human IL-18 was purchased MBL (Nagoya, Japan). The endotoxin levels were
Increased IL-18 and SAA levels in the synovial fluids of RA patients
Concentrations of IL-18 in synovial fluid samples from RA and OA patients were measured by specific ELISA. As shown in Fig. 1A, the levels of IL-18 in the synovial fluids from RA patients (mean ± SD 1171.8 ± 879.5 ng/ml) were significantly higher (p<0.001) than those of OA patients (mean ± SD 37.9 ± 126.6 ng/ml). We also measured the SAA concentrations of synovial fluids by means of specific ELISA using same samples. As shown in Fig. 1B, synovial SAA levels of RA patients were markedly elevated
Discussion
IL-18 is a member of IL-1 cytokine family that was originally identified as an IFN-γ inducing factor (Akira, 2000). Similar to IL-12, IL-18 stimulates Th1 differentiation and enhances natural killer cell cytotoxicity (Dinarello, 1999). It was demonstrated that RA synovial tissues showed increased expression of IL-18 mRNA expression and increased IL-18 protein synthesis as well as IL-18 receptor expression (Gracie et al., 1999). In the present study, we investigated the role of IL-18 in
References (16)
The role of IL-18 innate immunity
Current Opinion of Immunology
(2000)IL-18: A TH1-inducing, proinflammatory cytokines and new member of IL-1 family
Journal of Allergy and Clinical Immunology
(1999)- et al.
The putative fifth human serum amyloid A protein (SAA)-related gene “SAA5” is defined by SAA3
Biochemistry Biophysiology Research Communications
(1994) - et al.
The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein
Immunology Today
(1994) - et al.
A constitutively expressed serum amyloid A protein gene (SAA4) is closely linked to, and shares structural similarities with, an acute-phase serum amyloid A gene (SAA2)
Genomics
(1993) - et al.
Autocrine induction of collagenase by serum amyloid A-like and β2-microglobulin-like proteins
Science
(1989) - et al.
A proinflammatory role for IL-18 in rheumatoid arthritis
Journal of Clinical Investigation
(1999) - et al.
Local expression of acute phase seruma myloid A mRNA in rheumatoid arthritis synovial tissue and cells
Journal of Rheumatology
(1999)
Cited by (17)
Association between serum amyloid A and rheumatoid arthritis: A systematic review and meta-analysis
2022, Seminars in Arthritis and RheumatismCitation Excerpt :Previous study suggested that SAA augmented the inflammatory response in a cytokine-like fashion by attracting monocytes/macrophages, leukocytes and T lymphocytes, and that it facilitated neutrophil survival and endothelial activation and stimulated the production of proinflammatory mediators such as TNF, IL-1, IL-6, IL-8, and IL-17 [40]. And clinical evidence showed that SAA could be readily and locally produced by synovial cells in joints of RA patients [55], which stimulated the production of matrix metalloproteinases (MMPs) by chondrocytes and synovial fibroblasts, thereby inducing these cartilage-degrading proteinases and causing the chronic tissue injury in arthritis [56]. Under aforementioned condition, SAA plays a pathogenic role in joint, leading to the cartilage destruction by activating the receptor such as N-formyl peptide receptor-like 1 (FPRL1).
MTADV 5-MER peptide suppresses chronic inflammations as well as autoimmune pathologies and unveils a new potential target-Serum Amyloid A
2021, Journal of AutoimmunityCitation Excerpt :P2/A1 Fibroblasts (derived from no more than 10 cell passage [18]) were selected, because they are highly involved in chronic inflammations [34]. Moreover, SAA is upregulated in cytokine-stimulated fibroblasts [35,36] and conversely SAA stimulates chemokine and cytokine production in fibroblasts, including IL-6 and IL-1β, which are predominantly produced by these cells following SAA stimulation [37,38], generating uncontrolled vicious inflammatory cycle. SAA1 enhanced the release of IL-6 from the SAA-stimulated human fibroblasts, but inclusion of the 5-MP inhibited IL-6 (Fig. 2B and C) and IL-1β (Fig. 2D) release from these cells.
Cytokines and serum amyloid A in the pathogenesis of hepatitis C virus infection
2019, Cytokine and Growth Factor ReviewsCitation Excerpt :Various inflammatory cytokines, namely IL-1α, IL-1β, IL-6 and TNF-α upregulate SAA expression [17]. Although less frequently described, IL-17 and IL-18 have also been reported to induce SAA expression in keratinocytes, polyp epithelial cells or fibroblasts [37–39]. In situ hybridization revealed IL-1α and TNF-α expression in the liver tissue of HCV-positive patients.
Serum Amyloid A in Inflammatory Rheumatic Diseases: A Compendious Review of a Renowned Biomarker
2021, Frontiers in ImmunologyMicroarray for Quantitative Determination of Inflammatory Biomarkers in a Culture Medium
2020, Molecular Biology