scholarly journals Cytokine Networks in the Pathogenesis of Rheumatoid Arthritis

2021 ◽  
Vol 22 (20) ◽  
pp. 10922
Author(s):  
Naoki Kondo ◽  
Takeshi Kuroda ◽  
Daisuke Kobayashi
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Damage ◽  
Synovial Cell ◽  
Janus Kinase ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Cytokine Networks ◽  
Necrosis Factor

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation causing progressive joint damage that can lead to lifelong disability. The pathogenesis of RA involves a complex network of various cytokines and cells that trigger synovial cell proliferation and cause damage to both cartilage and bone. Involvement of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 is central to the pathogenesis of RA, but recent research has revealed that other cytokines such as IL-7, IL-17, IL-21, IL-23, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1β, IL-18, IL-33, and IL-2 also play a role. Clarification of RA pathology has led to the development of therapeutic agents such as biological disease-modifying anti-rheumatic drugs (DMARDs) and Janus kinase (JAK) inhibitors, and further details of the immunological background to RA are emerging. This review covers existing knowledge regarding the roles of cytokines, related immune cells and the immune system in RA, manipulation of which may offer the potential for even safer and more effective treatments in the future.

Differential regulation of granulocyte-macrophage colony-stimulating factor mRNA and protein expression in human thyrocytes and thyroid-derived fibroblasts by interleukin-1α and tumour necrosis factor-α

1996 ◽  
Vol 151 (2) ◽  
pp. 277-285 ◽  
Author(s):  
G Aust ◽  
A Hofmann ◽  
S Laue ◽  
S Ode-Hakim ◽  
W A Scherbaum
Keyword(s):  
Protein Expression ◽  
Tumour Necrosis Factor Α ◽  
Gm Csf ◽  
Tnf Α ◽  
Macrophage Colony Stimulating Factor ◽  
Interleukin 1Α ◽  
Macrophage Colony ◽  
Factor Α ◽  
Stimulating Factor ◽  
Necrosis Factor

Abstract In this study, we provide the first report on the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) by human thyroid epithelial cells. Primary cultures of highly purified thyrocytes and thyroid-derived fibroblasts (n=3) and three thyroid anaplastic and one largely papillary carcinoma cell lines were exposed to different potent GM-CSF stimulators, employing interleukin 1α (Il-1α) and tumour necrosis factor-α (TNF-α). Cytokine mRNA levels were monitored by semiquantitative reverse transcriptase-PCR including an internal heterologous competitor fragment after 3, 6 and 18 h of culture. Culture supernatants were assayed for GM-CSF using a highly sensitive ELISA (detection limit ≤ 0·5 pg/ml) after 24 h. Basal GM-CSF mRNA expression was higher in fibroblasts and SW 1736 cells compared with thyrocytes, C 634, 8505 C and HTh 74 cells. GM-CSF was spontaneously secreted by fibroblasts (means ± s.e.m.; 43 ± 15 pg/ml), SW 1736 (59 ± 4 pg/ml), HTh 74 (34 ± 4 pg/ml) and C 643 cells (12 ± 1 pg/ml) but not by thyrocytes and 8505 C cells. Treatment with Il-1α (10 U/ml) resulted in a marked increase of GM-CSF mRNA within 3 h and an increase or induction of protein expression in thyrocyte (2350 ± 214 pg/ml), fibroblast (5242 ± 1400 pg/ml), SW 1736 (20016 ± 280 pg/ml) and C 643 cultures (1285 ± 79 pg/ml). Stimulation with TNF-α (10 U/ml) yielded divergent results. No significant increase of GM-CSF mRNA or protein expression was found in thyrocytes although TNF-α receptor expression in these cells is well documented. Stimulation with TNF-α resulted in an increased GM-CSF production in fibroblasts (361 ± 14 pg/ml), HTh 74 (148 ± 51 pg/ml) and SW 1736 cultures (235 ± 43 pg/ml). TSH (10 mU/ml) did not stimulate GM-CSF secretion in thyrocytes and HTh 74 cells, both expressing the TSH receptor. Phorbol 12-myristate 13-acetate (10 ng/ml) enhanced GM-CSF mRNA and protein levels in all cell types investigated. Our data suggest that both thyrocytes and fibroblasts synthesize GM-CSF in response to Il-1α, but only fibroblasts respond to TNF-α with a significant increase in GM-CSF. Anaplastic thyroid carcinomas are potential GM-CSF producers. Journal of Endocrinology (1996) 151, 277–285

scholarly journals Granulocyte-Macrophage Colony-Stimulating Factor- and Tumor Necrosis Factor Alpha-Mediated Matrix Metalloproteinase Production by Human Osteoblasts and Monocytes after Infection withBrucella abortus

2010 ◽  
Vol 79 (1) ◽  
pp. 192-202 ◽  
Author(s):  
Romina Scian ◽  
Paula Barrionuevo ◽  
Guillermo H. Giambartolomei ◽  
Carlos A. Fossati ◽  
Pablo C. Baldi ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Colony Stimulating Factor ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α ◽  
Factor Alpha ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

ABSTRACTOsteoarticular complications are common in human brucellosis, but the pathogenic mechanisms involved are largely unknown. Since matrix metalloproteinases (MMPs) are involved in joint and bone damage in inflammatory and infectious diseases, we investigated the production of MMPs by human osteoblasts and monocytes, either uponBrucella abortusinfection or upon reciprocal stimulation with factors produced by each infected cell type.B. abortusinfection of the normal human osteoblastic cell line hFOB 1.19 triggered a significant release of MMP-2, which was mediated in part by granulocyte-macrophage colony-stimulating factor (GM-CSF) acting on these same cells. Supernatants from infected osteoblasts exhibited increased levels of monocyte chemoattractant protein 1 and induced the migration of human monocytes (THP-1 cell line). Infection withB. abortusinduced a high MMP-9 secretion in monocytes, which was also induced by heat-killedB. abortusand by the Omp19 lipoprotein fromB. abortus. These effects were mediated by Toll-like receptor 2 and by the action of tumor necrosis factor alpha (TNF-α) produced by these same cells. Supernatants fromB. abortus-infected monocytes induced MMP-2 secretion in uninfected osteoblasts, and this effect was mediated by TNF-α. Similarly, supernatants from infected osteoblasts induced MMP-9 secretion in uninfected monocytes. This effect was mediated by GM-CSF, which induced TNF-α production by monocytes, which in turn induced MMP-9 in these cells. These results suggest that MMPs could be potentially involved in the tissue damage observed in osteoarticular brucellosis.

scholarly journals Granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α in combination is a useful diagnostic biomarker to distinguish familial Mediterranean fever from sepsis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Tomohiro Koga ◽  
Kaori Furukawa ◽  
Kiyoshi Migita ◽  
Shimpei Morimoto ◽  
Toshimasa Shimizu ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Gm Csf ◽  
Tnf Α ◽  
Mediterranean Fever ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Factor Α ◽  
Stimulating Factor ◽  
Necrosis Factor

Abstract Objective To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis. Method We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis. Results Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%). Conclusion Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines.

scholarly journals Granulocyte-Macrophage Colony-Stimulating Factor Amplification of Interleukin-1β and Tumor Necrosis Factor Alpha Production in THP-1 Human Monocytic Cells Stimulated with Lipopolysaccharide of Oral Microorganisms

1998 ◽  
Vol 5 (3) ◽  
pp. 341-347 ◽  
Author(s):  
A. A. M. A. Baqui ◽  
Timothy F. Meiller ◽  
Jennifer J. Chon ◽  
Been-Foo Turng ◽  
William A. Falkler
Keyword(s):  
Rt Pcr ◽  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α ◽  
Factor Alpha ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Oral Microorganisms ◽  
Necrosis Factor

ABSTRACT Cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), are used to assist in bone marrow recovery during cancer chemotherapy. Interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) play important roles in inflammatory processes, including exacerbation of periodontal diseases, one of the most common complications in patients who undergo this therapy. A human monocyte cell line (THP-1) was utilized to investigate IL-1β and TNF-α production following GM-CSF supplementation with lipopolysaccharide (LPS) from two oral microorganisms, Porphyromonas gingivalis and Fusobacterium nucleatum. LPS ofP. gingivalis or F. nucleatum was prepared by a phenol-water extraction method and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and determination of total protein and endotoxin contents. Resting THP-1 cells were treated with LPS of P. gingivalis or F. nucleatum and/or GM-CSF (50 IU/ml) by using different concentrations for various time periods. Production of IL-1β and TNF-α in THP-1 cells was measured by solid-phase enzyme-linked immunosorbent assay. Reverse transcription (RT)-PCR was used to evaluate the gene expression of resting and treated THP-1 cells. IL-1β was not detected in untreated THP-1 cells. IL-1β production was, however, stimulated sharply at 4 h. GM-CSF amplified IL-1β production in THP-1 cells treated with LPS from both oral anaerobes. No IL-1β-specific mRNA transcript was detected in untreated THP-1 cells. However, IL-1β mRNA was detected by RT-PCR 2 h after stimulation of THP-1 cells with LPS from both organisms. GM-CSF did not shorten the IL-1β transcriptional activation time. GM-CSF plus F. nucleatum or P. gingivalis LPS activated THP-1 cells to produce a 1.6-fold increase in TNF-α production at 4 h over LPS stimulation alone. These investigations with the in vitro THP-1 model indicate that there may be an increase in the cellular immune response to oral endotoxin following GM-CSF therapy, as evidenced by production of the tissue-reactive cytokines IL-1β and TNF-α.

scholarly journals Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Tumor Necrosis Factor Alpha on Trypanosoma cruzi Trypomastigotes

1998 ◽  
Vol 66 (6) ◽  
pp. 2722-2727 ◽  
Author(s):  
Elizabeth Olivares Fontt ◽  
Patrick De Baetselier ◽  
Carlo Heirman ◽  
Kris Thielemans ◽  
Ralph Lucas ◽  
...  
Keyword(s):  
Necrosis Factor Alpha ◽  
Gm Csf ◽  
Tnf Α ◽  
No Release ◽  
Factor Alpha ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

ABSTRACT We have previously shown that the addition of exogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) to nonactivated mouse peritoneal macrophages (MPM) limitsTrypanosoma cruzi infections in vitro (E. Olivares Fontt and B. Vray, Parasite Immunol. 17:135–141, 1995). Lower levels of infection were correlated with a higher level of production of tumor necrosis factor alpha (TNF-α) in the absence of nitric oxide (NO) release. These data suggested that GM-CSF and/or TNF-α might have a direct parasitocidal effect on T. cruzi trypomastigotes, independently of NO release. To address this question, T. cruzi trypomastigotes were treated with recombinant murine GM-CSF (rmGM-CSF), recombinant murine TNF-α (rmTNF-α), or both cytokines in a cell-free system. Treatment with rmGM-CSF but not rmTNF-α caused morphological changes in the parasites, and most became spherical after 7 h of incubation. Both cytokines exerted a cytolytic activity on the trypomastigotes, yet the trypanolytic activity of rmTNF-α was more effective than that of rmGM-CSF. Viable rmGM-CSF- and rmTNF-α-treated parasites were less able to infect MPM than untreated parasites, and this reduction in infectivity was greatest for rmGM-CSF. Treatments with both cytokines resulted in more lysis and almost complete inhibition of infection. The direct parasitocidal activity of rmTNF-α was inhibited by carbohydrates and monoclonal antibodies specific for the lectin-like domain of TNF-α. Collectively, these results suggest that cytokines such as GM-CSF and TNF-α may directly control the level of T. cruzi trypomastigotes at least in vitro and so could determine the outcome of infection in vivo.

Granulocyte-macrophage colony-stimulating factor preferentially activates the 94-kD STAT5A and an 80-kD STAT5A isoform in human peripheral blood monocytes

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1206-1214 ◽  
Author(s):  
RL Rosen ◽  
KD Winestock ◽  
G Chen ◽  
X Liu ◽  
L Hennighausen ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Human Peripheral Blood ◽  
Janus Kinase ◽  
Lower Molecular Weight ◽  
Colony Stimulating Factor ◽  
Enhancer Element ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces immediate effects in monocytes by activation of the Janus kinase (JAK2) and STAT transcription factor (STAT5) pathway. Recent studies have identified homologues of STAT5, STAT5A, and STAT5B, as well as lower molecular weight variants of STAT5. To define the activation of the STAT5 homologues and lower molecular weight variant in human monocytes and monocytes differentiated into macrophages by culture in macrophage- CSF (M-CSF), we measured the GM-CSF induced tyrosine phosphorylation of STAT5A, STAT5B, and any lower molecular weight STAT5 isoforms. Freshly isolated monocytes expressed 94-kD STAT5A, 92-kD STAT5B, and an 80-kD STAT5A molecule. Whereas 94-kD STAT5A was clearly tyrosine phosphorylated and bound to the enhancer element, the gamma response region (GRR), of the Fc gamma RI gene, substantially less tyrosine phosphorylated STAT5B bound to the immobilized GRR element. Macrophages lost their ability to express the 80-kD STAT5A protein, but retained their ability to activate STAT5A. STAT5A-STAT5A homodimers and STAT5A- STAT5B heterodimers formed in response to GM-CSF. Therefore, activation of STAT5A predominates compared to STAT5B when assayed by direct immunoprecipitation and by evaluation of bound STATs to immobilized GRR. Selective activation of STAT5 homologues in addition to generation of lower molecular isoforms may provide specificity and control to genes expressed in response to cytokines such as GM-CSF.

Combined blockade of granulocyte-macrophage colony stimulating factor and interleukin 17 pathways potently suppresses chronic destructive arthritis in a tumour necrosis factor α-independent mouse model

2008 ◽  
Vol 68 (5) ◽  
pp. 721-728 ◽  
Author(s):  
C Plater-Zyberk ◽  
L A B Joosten ◽  
M M A Helsen ◽  
M I Koenders ◽  
P A Baeuerle ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Colony Stimulating Factor ◽  
Streptococcal Cell Wall ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Necrosis Factor

Objective:A pathogenic role for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)17 in rheumatoid arthritis (RA) has been suggested. In previously published work, the therapeutic potentials of GM-CSF and IL17 blockade in arthritis have been described. In the present study, the simultaneous blockade of both pathways in a mouse model for chronic arthritis was investigated to identify whether this double blockade provides a superior therapeutic efficacy.Methods:A chronic relapsing arthritis was induced in C57Bl/6 wild type (WT) and C57Bl/6 genetically deficient for IL17 receptor (IL17R knockout (KO)) mice by intra-articular injection of Streptococcal cell wall (SCW) fragments into knees on days 0, 7, 14 and 21. Treatments (intraperitoneal) were given weekly starting on day 14. Animals were analysed for inflammation, joint damage and a range of inflammatory mediators.Results:Joint swelling and cartilage damage were significantly reduced in the IL17R KO mice and in WT mice receiving anti-GM-CSF neutralising mAb 22E9 compared to isotype control antibodies. The therapeutic effect was significantly more pronounced in mice where IL17 and GM-CSF pathways were inhibited (eg, IL17R KO mice treated with 22E9 mAb). Tumour necrosis factor (TNF)α blockade had essentially no effect.Conclusion:Our data further support the therapeutic potentials of GM-CSF and IL17 blockade in a RA model that is no longer responsive to an established TNFα antagonist, moreover, our results suggest that concomitant inhibition of both pathways may provide the basis for a highly effective treatment of chronic RA in patients that are resistant to treatment by TNFα inhibitors.

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