mandag den 9. juli 2012

MicroRNA and ME

What is microRNA?

MiRNA (microRNA) is a large group of about 1000 different, very small RNA molecules, that regulate, how the information in the genes is translated into proteins in the cells. Here the proteins determine, how the cells work and develop. Another type of RNA molecules, mRNA (messengerRNA) determines, which proteins are expressed in the cell, while miRNAs determines the extent to which the proteins are expressed. Danish reference.

MiRNAs have the potential to be used as biomarker for a lot of diseases. They are widely used in cancer research. Exiqon, a company in Denmark, are experts in miRNA technology. You can learn more from their website. Danish readers can learn more from Biokemisk Forening.

In miRBase: the microRNA database you can search for information about any micro-RNA.

MicroRNAs as biomarker for ME

Shown by this paper, Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, micro-RNAs can maybe also be used as a biomarker for ME:

"There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the CFS/ME sufferers.

Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls.

Collectively these miRNAs have been associated with apoptosis, cell cycle, development and immune function. Changes in miRNAs in cytotoxic cells may reduce the functional capacity of these cells and disrupt effective cytotoxic activity along with other immune functions in CFS/ME patients."

MicroRNA, TLR, EBV and immune-mediated diseases

In my last post I wrote about TLR, LPS and ME. And now we can learn from the following abstracts, that microRNA, TLR and LPS are somehow connected. Epstein Bar Viruses also push the microRNAs around, likewise microRNAs are involved in all immune-mediated diseases:

A trio of microRNAs that control Toll-like receptor signalling
"Several miRNAs have been shown to be up-regulated in response to TLR ligands, and many directly target components of the TLR signalling system, revealing a whole extra level of control of TLR signalling which is being extensively researched. The dysregulation of miRNAs may be involved in many inflammatory diseases and cancers and thus merits further investigation. In this review, we focus in on a trio of miRNA which have proven to be key in many immune and inflammatory pathways; miR-155, miR-21 and miR-146."

MicroRNA in TLR signaling and endotoxin tolerance
"Toll-like receptors (TLRs) in innate immune cells are the prime cellular sensors for microbial components. TLR activation leads to the production of proinflammatory mediators and thus TLR signaling must be properly regulated by various mechanisms to maintain homeostasis. TLR4-ligand lipopolysaccharide (LPS)-induced tolerance or cross-tolerance is one such mechanism, and it plays an important role in innate immunity. Tolerance is established and sustained by the activity of the microRNA miR-146a, which is known to target key elements of the myeloid differentiation factor 88 (MyD88) signaling pathway, including IL-1 receptor-associated kinase (IRAK1), IRAK2 and tumor-necrosis factor (TNF) receptor-associated factor 6 (TRAF6). In this review, we comprehensively examine the TLR signaling involved in innate immunity, with special focus on LPS-induced tolerance. The function of TLR ligand-induced microRNAs, including miR-146a, miR-155 and miR-132, in regulating inflammatory mediators, and their impact on the immune system and human diseases, are discussed. Modulation of these microRNAs may affect TLR pathway activation and help to develop therapeutics against inflammatory diseases."

Differential regulation of miR-21 and miR-146a by Epstein-Barr virus-encoded EBNA2
"The discovery of microRNA (miR) represents a novel paradigm in RNA-based regulation of gene expression and their dysregulation has become a hallmark of many a tumor. In virally associated cancers, the host-pathogen interaction could involve alteration in miR expression. Epstein-Barr virus (EBV)-encoded EBNA2 is indispensable for the capacity of the virus to transform B cells in vitro. Here, we studied how it affects cellular miRs. Extensive miR profiling of the virus-infected and EBNA2-transfected B lymphoma cells revealed that oncomiR miR-21 is positively regulated by this viral protein. Conversely, Burkitt's lymphoma (BL) cell lines infected with EBNA2 lacking P3HR1 strain did not show any increase in miR-21. EBNA2 increased phosphorylation of AKT and this was directly correlated with increased miR-21. In contrast, miR-146a was downregulated by EBNA2 in B lymphoma cells. Low miR-146a expression correlates with an elevated level of IRAK1 and type I interferon in EBNA2 transfectants. Taken together, the present data suggest that EBNA2 might contribute to EBV-induced B-cell transformation by altering miR expression and in particular by increasing oncomiR-like miR-21 and by affecting the antiviral responses of the innate immune system through downregulation of its key regulator miR-146a."

MicroRNAs: emerging regulators of immune-mediated diseases
"Recently, the role of miRNAs in the development of immune cells and the maintenance of immune system homeostasis gained attention and the involvement of miRNAs in the pathogenesis of several immune system diseases has emerged. This review focuses on the role of miRNAs in autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis) and inflammatory pathologies of distinct organ (atherosclerosis, osteoarthritis, atopic eczema) and/or systemic locations such as allergy. The role of miRNAs, their predicted and known mRNA targets and description of their actions in physiological immune reactions and in the pathological processes ongoing in immune-mediated human disorders will be discussed. Finally, miRNA-based diagnostics and therapeutic potentials will be highlighted."

Pieces of puzzles: ME after EBV infection, activated TLRs, downregulated microRNAs, translocated LPS, changed mRNA in purinergic signalling and TLR4 after exercise, reduced NK cytotoxic activity, Rituximab that helps some ME patients…are the scientists about to solve the puzzle?

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