RNAs are oneof the most critical molecular cellular constituents, rRNA and tRNA areessential for the transcription and replication of DNA, although these codingRNAs stand for a large proportion of the total RNA, the genome also containnoncoding RNA which are also critical in the cell. Non-coding RNAs aremanifested in several different ways such as miRNAs and lncRNAs, initiallytheses ncRNAs were thought to be ‘junk’ and had no function but it is now knownthat ncRNAs play significant roles in the cells.
It has been shown that miRNAscan control the expression of TLRs and can also function as an oncogene.LncRNAs can regulate cell signalling cytokines and transcriptional regulators,which if are irregularly expressed result in inflammatory diseases. IntroductionRNA may beconsidered one of the most critical biological constituents of a cell, and isrevolved around the central dogma of life.
Within the cell RNA especially mRNAand tRNA (coding RNA) are critical for the replication of DNA, the majority ofRNA in the cell is rRNA (~90%), but it has been shown there is a significantamount of non-coding RNA present in the cell such as miRNAs and piRNAs, can bevery small, under 200 nucleotides, and can be in present in very high levels incertain cell types (Palazzo and Lee, 2015). Non-codingRNAs are hypothesised to play many cellular roles, many play an important rolein immune function, and two significant lncRNAs in immune function areMicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs). miRNAs are createdthrough the transcription of RNA polymerases II, and are involved in post-transcriptionalgene regulation (Cannell et al., 2008). Secondlylong noncoding RNAs (IncRNAs), which are defined as being over 200 nucleotideslong. LncRNAs are show to be involved in processes of gene regulationincluding, chromatin modification, transcriptional modification,post-transcriptional modifications regulation of genomic imprinting andmodulation od miRNA regulation. Main bodyLncRNAsIncRNAs canplay a significant role in the immune system, mainly mediated by proteinbinding, and lncRNAs specifically target the nuclear factor-kB (NF-kB) andsignal transducer and activator of transcription 3 (STAT3). Guttman et al.
2009suggested a role for lncRNAs in the innate immune system in which lncRNAs aredifferentially expressed following the activation of monocytes, macrophages, dendriticcells, and fibroblasts, and viral infection (heward and Lindsay, 2009). TNF?regulate many lncRNAs, which show selective expression in response cytokines(Rapicavoli et al., 2013), such as THRIL, Lethe and Cox2. One lncRNAs,THRIL is found to regulate TNFa (tumour necrosis factor alpha), which is a cellsignalling protein/ cytokine.
THRIL has been shown to induce the expression ofmultiple inflammatory genes such as IL6 (Heward and Lindsay, 2014). Transcriptomicand gene knockdown studies revealed that THRIL (previous known as? linc1992),was critical in the expression of several immune related genes includingcytokines and transcriptional and post-transcriptional regulators of TNFa (liet al, 2013). There has also been someclinical significant concerning THRIL, in which it is associated with severalinflammatory diseases such as inflammatory bowel and rheumatoid arthritis, aswell as some associations with the childhood disease Kawasaki disease. Lethe, apseudogene has also shown to be induced follow exposure to two genes IL-1? andGR agonist (ref),and can also block NF-kB- DNA binding and can inhibit the inflammatory responseto TNF? and IL-1? (Heward and Lindsay, 2014).
Lethe dysregulation can play arole in several immune diseases, especially hyperglycemia where there in aninduced ROS production. Zgheib et al. have indicated that Lethe is involved inthe regulation of ROS production, Lethe controls the regulation of ROS throughthe control of NOX2 gene expression via NFkB signalling. Cox2 hasbeen shown to mediate the induction and repression of gene expression in mousemacrophages, the lincRNA-Cox2 complex can induce the expression ofapproximately 700 genes, which are involved in the immune response includingIL6 and CcL5. Until recently, the function of lincRNA-Cox2 was massively underdescribed, but whole- transcriptome profiling revealed both an activating andrepressing behaviour of immune genes by lincRNA-Cox2 (Capenter et al., 2013). MiRNAsThere arelimited studies on the roles of miRNAs in the immune system, although there aresome previous studies, which have extensively explored the roles of noncodingRNAs in the immune system, such as miR-155 functioning as an oncogene, andmiR-155 is also triggered/ upregulated in response to toll like receptor (TLR)signalling. MiR-155 havebeen hypothesised to play a significant role in the development of chroniclymphocytic leukaemia (CLL), miR-155 levels in patients with CLL increases as Bcells progress to monoclonal B-cell lymphocytosis (MBL) to CLL (Ferrajoli etal.
, 2013), there is also an significant expression of miR-155 in the plasma ofpatients after treatment shown in Ferrajoli et al 2013. miR-155 expressionrepresents a good biomarker for CLL, due to the high level gene expressioncontrol it has over B cells. Toll likereceptors (TLR), are key in the innate immune system, they can recognisepathogens and active immune response such as the inflammatory response, resultingcytokine production and destruction of the pathogenic cell.
The receptors areexpressed on the membrane on most cells including dendritic cells, macrophagesand natural killer cells, because of the extreme response of these cells theyrequire tight control. It is becoming more evident that some miRNAs areresponsible for regulating the expression of TLRs. Microarraybased technologies can be used to identify miRNAs which are induced inmacrophages after exposure to cytokines (O’Connell et al., 2006), miRNA-155 hasbeen shown to be induced following exposure to the cytokine IFN-?, as well asTLR ligands.
With this finding it can be assumed that miRNA-155 is a target forbroad range inflammatory mediators, and play a role in stimulating the cytokinecontrolled inflammatory response. ConclusionNon codingRNAs play a significant cellular role and can have great implications on theimmune system. Two important non coding RNA are lncRNAs (Long non coding RNAs)and miRNAs (micro RNA), ncRNA are formed when the DNA is transcribed into a non-codingRNA which is not translated into a protein therefore stays as an RNA molecule.Non coding RNA molecules have been shown to play a significant role in manyimmune functions, lncRNAs can regulate the cytokine TNFa which can causeinflammatory diseases and can also induce the expression of IL6 ans Ccl6.
MicroRNAshave been shown to play an import role as an oncogene, especially miR-155 whichis associated with the development of chronic lymphocytic leukaemia from monoclonalB-cell lymphocytosis, and can be used as a marker to diagnose the developmentof the diseases as well as track the effectiveness of the treatment. MicroRNAsalso play a role in the inflammatory response, and are induced following cytokineexposure, because miR-155 can function as an oncogene and is also a target forinflammatory mediators we must consider if there is any link between cancer andinflammation mediated by miR-155.