IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis

Erlandsson, Malin C.; Silfverswärd, Sofia Töyrä; Nadali, Mitra; Turkkila, Minna; Svensson, Mattias; Jonsson, Ing-Marie; Andersson, Karin; Bokarewa, Maria

doi:10.1016/j.bbadis.2017.06.002

Cited by 40 publications

(46 citation statements)

References 85 publications

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“…This observation reveals that TXNDC5 can up-regulate IL-6 levels by suppressing IGFBP1 expression. IGF-1 receptor signalling was shown recently to contribute to IL-6 production in RA [36], which supports our findings. The IL-6 inhibitor, tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, shows outstanding efficacy in RA [34,35].…”

Section: Discussionsupporting

confidence: 93%

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TXNDC5 contributes to rheumatoid arthritis by down-regulating IGFBP1 expression

Wu³

et al. 2017

Clinical and Experimental Immunology

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The thioredoxin domain-containing 5 (TXNDC5) gene is associated with susceptibility to rheumatoid arthritis (RA) and exhibits increased expression in the synovial tissues. TXNDC5 is also associated strongly with diabetes, a metabolic disease characterized by interrupted insulin signalling. This study investigated whether TXNDC5 contributes to RA via the insulin signalling pathway. In this study, RA synovial fibroblast-like cells (RASFs) transfected with an anti-TXNDC5 small interfering RNA (siRNA) were analysed with an insulin signaling pathway RT profiler polymerase chain reaction (PCR) array and an insulin resistance RT profiler PCR array. The PCR arrays detected significantly increased expression of insulin-like growth factor binding protein 1 (IGFBP1) in RASFs with suppressed TXNDC5 expression. The result was verified using real-time PCR and Western blot analyses. Significantly elevated IGFBP1 expression and decreased interleukin (IL)-6 secretion were also detected in culture medium of transfected RASFs. Furthermore, decreased IGFBP1 mRNA and protein expression levels were detected in RA synovial tissues. Additionally, significantly increased apoptosis and decreased cell proliferation and cell migration were observed in RASFs transfected with the anti-TXNDC5 siRNA, whereas transfection with the anti-IGFBP1 siRNA or a mixture of the anti-IGFBP1 and anti-TXNDC5 siRNAs restored normal cell proliferation, migration and IL-6 level in RASFs. Insulin-like growth factor (IGF) has potent prosurvival and anti-apoptotic functions, and IGFBP1 can suppress IGF activity. Based on the results of the present study, we suggest that TXNDC5 contributes to abnormal RASF proliferation, migration and IL-6 production by inhibiting IGFBP1 expression.

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Section: Discussionsupporting

confidence: 93%

“…Thus, we suggest that TXNDC5 decreases IL-6 production rather than the production of other cytokines by regulating IGFBP1 expression. IGF-1 receptor signalling was shown recently to contribute to IL-6 production in RA [36], which supports our findings.…”

Section: Discussionsupporting

confidence: 93%

TXNDC5 contributes to rheumatoid arthritis by down-regulating IGFBP1 expression

Wu³

et al. 2017

Clinical and Experimental Immunology

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“…Under physiological conditions, these two signaling pathways operate independently and mediate respectively metabolic and antibacterial functions. Under inflammatory conditions created by obesity and RA, activation of IGF1R and TLR4 synergize to trigger adaptive immune responses and T cell differentiation in the target adipose and synovial tissues [ 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

High Expression of STAT3 in Subcutaneous Adipose Tissue Associates with Cardiovascular Risk in Women with Rheumatoid Arthritis

Nadali

Pullerits

Andersson

et al. 2017

IJMS

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Despite the predominance of female patients and uncommon obesity, rheumatoid arthritis (RA) is tightly connected to increased cardiovascular morbidity. The aim of this study was to investigate transcriptional activity in the subcutaneous white adipose tissue (WAT) with respect to this disproportionate cardiovascular risk (CVR) in RA. CVR was estimated in 182 female patients, using the modified Systematic Coronary Risk Evaluation scale, and identified 93 patients with increased CVR. The overall transcriptional activity in WAT was significantly higher in patients with CVR and was presented by higher serum levels of WAT products leptin, resistin and IL-6 (all, p < 0.001). CVR was associated with high WAT-specific transcription of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor NF-kappa-B p65 subunit (RELA), and with high transcription of serine-threonine kinase B (AKT1) in leukocytes. These findings suggest Interleukin 6 (IL-6) and leptin take part in WAT-specific activation of STAT3. The binary logistic regression analysis confirmed an independent association of CVR with IL-6 in serum, and with STAT3 in WAT. The study shows an association of CVR with transcriptional activity in WAT in female RA patients. It also emphasizes the importance of STAT3 regulatory circuits for WAT-related CVR in RA.

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“…In addition, RA is a self-maintaining inflammatory disease, in which the destruction of the adjacent bone is induced by inflammation ( 33 ). Studies have demonstrated that inflammatory cytokines, including IL-1β, IL-6, IL-8, MMP-1 and MMP-13, serve a key role in the pathogenesis of RA ( 34 , 35 ). The results of the present study indicated that inhibition of miR-143-3p significantly inhibited the production of these inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the present study indicated that IGF1R and IGFBP5 are target genes of miR-143-3p. It has been reported that IGF-1R signaling contributes to T cell-dependent inflammation in RA ( 35 ). Furthermore, it has been suggested that MMP-13 and IGFBP5 are important factors that mediate the development of OA ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

miR-143-3p regulates cell proliferation and apoptosis by targeting IGF1R and IGFBP5 and regulating the Ras/p38 MAPK signaling pathway in rheumatoid arthritis

Yang

Wang²,

Pan³

et al. 2018

Exp Ther Med

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It has been demonstrated that the deregulation of microRNAs (miRNAs) affects the development of rheumatoid arthritis (RA). The primary objective of the current study was to determine the role of miR-143-3p in the progression of RA. The expression of miR-143-3p in synovium taken from patients with RA was assessed by reverse transcription-quantitative polymerase chain reaction. The expression of miR-143-3p was higher in synovium tissues of RA than that of osteoarthritis (OA). The decreased expression of miR-143-3p suppressed cell proliferation and promoted apoptosis in vitro. In addition, inhibition of miR-143-3p decreased levels of inflammatory cytokines, as determined by an enzyme-linked immunosorbent assay. IGF1R and IGFBP5 were found to be the target genes of miR-143-3p, and it was demonstrated that miR-143-3p regulated the proliferation and apoptosis of MH7A cells by targeting IGF1R and IGFBP5. Furthermore, TNF-α treatment stimulated the Ras/p38 mitogen activated protein kinase (MAPK) signaling pathway, whereas miR-143-3p inhibition suppressed it. The results of the current study indicate that miR-143-3p may regulate cell proliferation and apoptosis by targeting IGF1R and IGFBP5 expression and regulating the Ras/p38 MAPK signaling pathways. Therefore, miR-143-3p may be a novel therapeutic target in RA.

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IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis

Abstract: IGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA.

Cited by 40 publications

References 85 publications

TXNDC5 contributes to rheumatoid arthritis by down-regulating IGFBP1 expression

TXNDC5 contributes to rheumatoid arthritis by down-regulating IGFBP1 expression

High Expression of STAT3 in Subcutaneous Adipose Tissue Associates with Cardiovascular Risk in Women with Rheumatoid Arthritis

miR-143-3p regulates cell proliferation and apoptosis by targeting IGF1R and IGFBP5 and regulating the Ras/p38 MAPK signaling pathway in rheumatoid arthritis

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