Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjögren's syndrome
Highlights
► In Sjögren patients miRNA 146a/b, TRAF6 are overexpressed. ► IRAK 1 is repressed. ► Specific for Sjögren.
Introduction
MicroRNAs are endogenous non-coding RNAs, however, regulating gene expression, and they are important in a wide range of physiological processes [1]. MicroRNA (miR) expression profile have become widely studied as potential biomarkers of various diseases as autoimmune diseases like multiple sclerosis [2], rheumatoid arthritis (RA) [3], [4], systemic lupus erythematosus (SLE) [5], Sjögren's syndrome (SS) [6], [7], [8] or cancer [9]. However, there is still a rather great number of contradictions in the interpretation of the findings concerning the over or underexpression of the various miR groups depending on the types of cells tested in the variuos diseases. For example, microRNA-146a (miR-146a) was found to be underexpressed in the peripheral mononuclear cells of SLE patients [5] but it was overexpressed both in peripheral blood and the synovial tissue of RA subjects [3]. In the salivary glands of patients with Sjögren's syndrome representing high focus scores, the decrease in miR-17–92 was observed compared to those with low focus score [6], [7]. Furthermore, the expression analysis of miRs that are predicted to target Ro/SSA and La/SSB autoantigens revealed differential expression of certain miRs in the salivary gland tissues, salivary gland epithelial cells and peripheral blood mononuclear cells of patients with SS [8].
In the regulation of autoimmunity, myeloproliferation and cancer miR-146 is regarded as a significant brake. MiR-146a is a member of the miR-146 miRNA family, consisting of two evolutionary conserved miRNA genes; miR-146a and miR-146b. In people, these loci are located on separate chromosomes, in quite unrelated sequence contexts, but differ in their mature sequence only by 2 nt at the 3′ end [9]. Both genes respond to LPS in human monocytes, but only miR-146a is processed to a mature form, and the induction of expression of miR-146a is NF-κB dependent [10]. These authors suggest that miR-146a acts as a negative feedback regulator of the immune response by targeting two genes (adapter proteins) TRAF6 (TNF receptor-associated factor 6) and IRAK1 (IL-1 receptor-associated kinase 1), that are crucial for proinflammtory signalling [10]. In addition, miR-146 deficiency in T regs results in a defect in their suppressor function and dysregulated IFNγ responses, seemingly through an increase in signal transducer and activator 1 (Stat1) expression and activation [11], [12].
In the regulation of TLR4 signalling, MyD88 serves as one of the scaffold proteins for members of the IRAK family of kinases, including IRAK1, which then activates TRAF6 initiating, via more steps, the proteosomal degradation of IκBα and the production of free NF-κB. Free NF-κB (the p65–p50 dimer) moves into the nucleus and activates the transcription of genes encoding inflammatory molecules, like interferons and cytokines [13].
Therefore, in the current study, we investigated the expression of miR-146a and miR-146b in the peripheral mononuclear cells of patients with Sjögren's syndrome compared to the cells of healthy controls. Concurrently, we also measured the expression of the IRAK1, IRAK4, and TRAF6 genes which are supposed to be under the control of miR-146a [10], [13], [14], [15].
Section snippets
Patients
Twenty-one patients with primer Sjögren's syndrome (pSS) (1 male, 20 female; mean age 60.5 ± 12.4 years) were enrolled in the present study, recruited from the Autoimmune Outpatient Clinic of the Division of Clinical Immunology, 3rd Department of Medicine, Medical and Health Science Center, University of Debrecen. The diagnosis of pSS (primer Sjögren) was established according to the European–American consensus criteria [16]. These patients did not receive any immunosuppressive or
Overexpression of microRNA-146a and microRNA-146b in patients with Sjögren's syndrome as compared with normal controls
The relative expression of miR-146a and miR-146b was sigificantly higher in the mononuclear cells of patients with Sjögren's syndrome than in those of the normal controls (miR-146a: Sjögren patents: 2.91 ± 2.53 versus 1.0, p < 0.001; miR-146b: Sjögren's patients: 2.13 ± 2.10 versus 1.0, p < 0.001). The values of controls are not documented. These data are shown in Fig. 1. (In consequence of the relatively high number of cases, the data are presented in box-plot and not in dot-plot diagrams.)
Underexpression of IRAK1 and overexpression of TRAF6 genes in patients with Sjögren's syndrome as compared with normal controls
The
Discussion
IL-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) are two key adaptor molecules downstream of Toll-like and IL-1 receptors (TIRs) signalling pathway [17], [18]. Evidence has shown that miR-146a can inhibit the expression of IRAK1 and TRAF6 [9], [19], [20], impairs NF-κB activity [19], and suppresses the expression of NF-κB target genes such as IL-6, IL-8, IL-1β and TNFα [4]. It has to be stressed that the expression rate and suppressive effects of miR-146a,
Conflict of interest
No disclosure to report.
Acknowledgments
We thank Professor Dr. Gyula Szegedi for the important scientific discussions, furthermore, Katalin Deák, Ildikó Kovács and Andrea Nagy for the excellent technical help. This work was supported by the grants of the Hungarian Research Fund (OTKA 71883) and the TÁMOP 4.2.1./B-09/1/KONV-2010-0007 project, which was co-financed by the European Union and the European Social Fund.
References (29)
- et al.
MicroRNAs in Sjögren's syndrome as a prototypic autoimmune disease
Autoimmun Rev
(2010) - et al.
Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses
Cell
(2010) - et al.
MicroRNA control of lymphocyte differentiation and function
Curr Opin Immunol
(2011) - et al.
A defect in the protein kinase C system in T cells from patients with systemic lupus erythematosus
Clin Immunol Immunopathol
(1991) - et al.
Differential regulation of interleukin-1 receptor associated kinase-1 (IRAK-1) and IRAK2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease
J Biol Chem
(2010) - et al.
A polymorphism in3’UTR of interleukin-1 receptor associated kinase (IRAK1), a target gene of miR-146a, is associated with rheumatoid arthritis susceptibility
Joint Bone Spine
(2010) - et al.
MicroRNAs: biogenesis, function and applications
Curr Opin Mol Ther
(2009) - et al.
MicroRNA miR-326 regulates t(H)-17 differentiation and is associated with the pathogenesis of multiple sclerosis
Nat Immunol
(2009) - et al.
Expression of microRNA-146 in rheumatoid arthritis synovial tissue
Arthritis Rheum
(2008) - et al.
Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients
Arthritis Res Ther
(2008)
MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins
Arthritis Rheum
MicroRNA profiling of minor salivary glands identifies disease and inflammation biomarkers in Sjögren's syndrome patients
Arthitis Rheum
Cellular microRNAs (miRNAs) and Sjögren's syndrome: candidate regulators of autoimmune response and autoantigen expression
J Autoimmun
miR-146 is a significant brake on autoimmunity, myeloproliferation and cancer in mice
J Exp Med
Cited by (120)
Evolving understandings for the roles of non-coding RNAs in autoimmunity and autoimmune disease
2023, Journal of AutoimmunityMicroRNA regulation in autoimmune diseases
2022, Post-transcriptional Gene Regulation in Human Disease: Volume 32Epigenetic in precision medicine in autoimmune and inflammatory-mediated disorders
2021, Epigenetics in Precision MedicineA comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases
2020, Immunology LettersCitation Excerpt :Several factors can underlie this irregularity [52,55–76]. Evidence has shown that genetic polymorphisms in miRNAs genes and also their target molecules influence the effects of miRNAs on their targets and can even alter the target molecules response pattern to the miRNAs-induced effects [52,55]. Competing endogenous RNAs (ceRNAs) or miRNA sponges can also interfere in binding of target molecules to miRNAs [62–65].
- 1
Joint last authors contributing equally to this paper.