The antibody atliximab attenuates collagen-induced arthritis by neutralizing AIMP1, an inflammatory cytokine that enhances osteoclastogenesis

Hong, Shin Hee; Cho, Jin Gu; Yoon, Kang Jun; Lim, Dae‐Seog; Kim, Chul Hoon; Lee, Sang Won; Park, Sang Gyu

doi:10.1016/j.biomaterials.2014.12.017

Cited by 19 publications

(17 citation statements)

References 53 publications

(47 reference statements)

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“…TNF-α)-dependent apoptosis (41). The antibody atliximab was reported to neutralize the expression of AIMP1 and then block the AIMP1-mediated production of inflammatory cytokines, ultimately attenuating collagen-induced arthritis (42). Accordingly, we speculate that EEF1E1 may also be involved in inflammation of AS by upregulating p53 and pro-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Screening of underlying genetic biomarkers for ankylosing spondylitis

Fan

et al. 2019

Mol Med Report

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Genetic biomarkers for the diagnosis of ankylosing spondylitis (AS) remain unreported except for human leukocyte antigen B27 (HLA-B27). Therefore, the aim of the present study was to screen the differentially expressed genes (DEGs), and those that also possess differential single nucleotide polymorphism (SNP) loci in the whole blood of AS patients compared with healthy controls by integrating two mRNA expression profiles (GSE73754 and GSE25101) and SNP microarray data (GSE39428) collected from the Gene Expression Omnibus (GEO). Using the t-test, 1,056 and 1,073 DEGs were identified in the GSE73754 and GSE25101 datasets, respectively. Among them, 234 DEGs were found to be shared in both datasets, which were subsequently overlapped with 122 differential SNPs of genes in the GSE39428 dataset, resulting in identification of two common genes [eukaryotic translation elongation factor 1 epsilon 1 ( EEF1E1 ) and serpin family A member 1 ( SERPINA1 )]. Their expression levels were significantly upregulated and the average expression log R ratios of SNP sites in these genes were significantly higher in AS patients than those in controls. Function enrichment analysis revealed that EEF1E1 was involved in AS by influencing the aminoacyl-tRNA biosynthesis, while SERPINA1 may be associated with AS by participating in platelet degranulation. However, only the genotype and allele frequencies of SNPs (rs7763907 and rs7751386) in EEF1E1 between AS and controls were significantly different between AS and the controls, but not SERPINA1 . These findings suggest that EEF1E1 may be an underlying genetic biomarker for the diagnosis of AS.

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Section: Discussionmentioning

confidence: 99%

Screening of underlying genetic biomarkers for ankylosing spondylitis

Fan

et al. 2019

Mol Med Report

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“…Approximately 20 μ g of total protein was separated by SDS-polyacrylamide gel electrophoresis (PAGE). Proteins were transferred onto polyvinylidene fluoride membranes using the Trans-Blot semi-dry transfer kit (Bio-Rad, Hercules, CA, USA), followed by blocking for 30 min with 5% non-fat dry milk prepared in Tris-buffered saline (TBS) containing 0.1% Tween-20 (TBS-T), and then incubated with the appropriate primary antibodies diluted in 1% BSA solution at 4 °C for 16 h. The primary antibodies were anti-TGF β RII (1 : 500, Abcam, Cambridge, UK), anti-TGF β RI (1 : 500, Abcam), anti-Smad1/5/8P (1 : 1000, Cell Signaling, Danvers, MA, USA), anti-Smad2P (1 : 1000, Cell Signaling), anti-Smad2 (1 : 1000, Cell Signaling), anti-Col-I (1 : 1000, Abcam), Agg (1 : 1000, Abcam), Smad3 (1 : 1000, Cell Signaling), Tubulin (1 : 1000, Abcam), Customized AIMP1 (1 : 1000, Hong et al 60 ), anti-Col II (1 : 1000, Millipore, Darmstadt, Germany), and Lamin A/C (1 : 1000, Millipore). Membranes were washed four times for 10 min with TBS-T and incubated with horseradish peroxidase-conjugated secondary antibodies (0.1 μ g/ml; Santa Cruz Biotechnology, Dallas, TX, USA).…”

Section: Methodsmentioning

confidence: 99%

AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal

Ahn

Kumar

et al. 2016

Cell Death Dis

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Dedifferentiation and degeneration of chondrocytes critically influences the efficiency of cartilage repair. One of the causes is the defect of transforming growth factor (TGF)-β signaling that promotes chondrogenic differentiation and degeneration. In the present study, we found that aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) negatively regulates TGF-β signaling via interactions with Smad2 and Smad3 in immunoprecipitation assay and luciferase assay. In addition, we observed that the AIMP1 expression level was significantly increased in osteoarthritis (OA) patient-derived degenerated chondrocytes compared with healthy control. So, we hypothesized that downregulation of AIMP1 using small-interfering RNA (siRNA) technology in dedifferentiated (collected at passage #6) and degenerated (obtained from OA-affected areas) chondrocytes could lead to recover TGF-β signaling in both chondrocytes. Indeed, AIMP1 downregulation restored TGF-β signaling by promoting phosphorylation of Smad2 and Smad3, which shows redifferentiated characteristics in both dedifferentiated and degenerated chondrocytes. Additionally, implantation analyses using in vivo mouse model clearly showed that AIMP1 downregulation resulted in the increased chondrogenic potential as well as the enhanced cartilage tissue formation in both dedifferentiated and degenerated chondrocytes. Histological analyses clarified that AIMP1 downregulation increased expression levels of collagen type II (Col II) and aggrecan, but not Col I expression. Taken together, these data indicate that AIMP1 downregulation using siRNA is a novel tool to restore TGF-β signaling and thereby increases the chondrogenic potential of dedifferentiated/degenerated chondrocytes, which could be further developed as a therapeutic siRNA to treat OA.

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“…AIMp1 is a secreted inflammatory cytokine previously reported to be released from a variety of cell types in response to cell stress and other stimuli 29,40‐43 . Recent work has substantially clarified the function of AIMp1, the DC expression of which was demonstrated to be essential for T H 1 polarization 29 .…”

Section: Resultsmentioning

confidence: 99%

MHC class I and II peptide homology regulates the cellular immune response

et al. 2020

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Mammalian immune responses are initiated by “danger” signals––immutable molecular structures known as PAMPs. When detected by fixed, germline encoded receptors, pathogen‐associated molecular pattern (PAMPs) subsequently inform the polarization of downstream adaptive responses depending upon identity and localization of the PAMP. Here, we report the existence of a completely novel “PAMP” that is not a molecular structure but an antigenic pattern. This pattern––the incidence of peptide epitopes with stretches of 100% sequence identity bound to both dendritic cell (DC) major histocompatibility (MHC) class I and MHC class II––strongly induces TH1 immune polarization and activation of the cellular immune response. Inherent in the existence of this PAMP is the concomitant existence of a molecular sensor complex with the ability to scan and compare amino acid sequence identities of bound class I and II peptides. We provide substantial evidence implicating the multienzyme aminoacyl‐tRNA synthetase (mARS) complex and its AIMp1 structural component as the key constituents of this complex. The results demonstrate a wholly novel mechanism by which T‐helper (TH) polarization is governed and provide critical information for the design of vaccination strategies intended to provoke cell‐mediated immunity.

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The antibody atliximab attenuates collagen-induced arthritis by neutralizing AIMP1, an inflammatory cytokine that enhances osteoclastogenesis

Cited by 19 publications

References 53 publications

Screening of underlying genetic biomarkers for ankylosing spondylitis

Screening of underlying genetic biomarkers for ankylosing spondylitis

AIMP1 downregulation restores chondrogenic characteristics of dedifferentiated/degenerated chondrocytes by enhancing TGF-β signal

MHC class I and II peptide homology regulates the cellular immune response

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