Deepti Malik, Aman Sharma,Ashvinder Raina, Deepak Kaul
Background: Both clinical and experimental evidences suggest that over expression of IL-17 and CCL5 induces synovial inflammation and joint destruction leading to rheumatoid arthritis (RA). The present study investigated the inter-relationship between miR-2909 and the genes recognized widely to play crucial role in the pathogenesis of ‘RA’.
Methods: Expression levels of genes coding for IL-6, IFN-γ, Rig-1, IL-17, CCL5, and Sp1 within peripheral blood mononuclear cells (PBMCs) derived from ‘RA’ and control subjects were analyzed using quantitative real time PCR and western blotting. Sequence analysis of coding region and 3´UTR region of KLF4 within PBMCs from ‘RA’ and control subjects was analyzed using Clustal W software.
Results: Our study revealed that PBMCs from ‘RA’ subjects possessed mutant miR-2909 which was unable to repress KLF4 gene expression. The uncontrolled expression of KLF4 led to the increased expression of genes coding for IL-6, IL-17, CCL5, IFN-γ and Rig-1. Moreover, the ability of KLF4 to regulate the expression of above-mentioned genes was verified by down-regulation of KLF4 gene in PBMCs derived from ‘RA’ subjects.
Conclusion: Based upon the study, we propose that mutant miR-2909 may contribute to the initiation of ‘RA’ through its inability to repress KLF4 gene expression thereby resulting in the uncontrolled expression of KLF4 which in turn ensures predominant Th17 immune response having CCL5-induced high chemotactic activity.