RNAs are one
of the most critical molecular cellular constituents, rRNA and tRNA are
essential for the transcription and replication of DNA, although these coding
RNAs stand for a large proportion of the total RNA, the genome also contain
noncoding RNA which are also critical in the cell. Non-coding RNAs are
manifested in several different ways such as miRNAs and lncRNAs, initially
theses ncRNAs were thought to be ‘junk’ and had no function but it is now known
that ncRNAs play significant roles in the cells. It has been shown that miRNAs
can 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.
RNA may be
considered one of the most critical biological constituents of a cell, and is
revolved around the central dogma of life. Within the cell RNA especially mRNA
and tRNA (coding RNA) are critical for the replication of DNA, the majority of
RNA in the cell is rRNA (~90%), but it has been shown there is a significant
amount of non-coding RNA present in the cell such as miRNAs and piRNAs, can be
very small, under 200 nucleotides, and can be in present in very high levels in
certain cell types (Palazzo and Lee, 2015).
RNAs are hypothesised to play many cellular roles, many play an important role
in immune function, and two significant lncRNAs in immune function are
MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs). miRNAs are created
through the transcription of RNA polymerases II, and are involved in post-transcriptional
gene regulation (Cannell et al., 2008).
long noncoding RNAs (IncRNAs), which are defined as being over 200 nucleotides
long. LncRNAs are show to be involved in processes of gene regulation
including, chromatin modification, transcriptional modification,
post-transcriptional modifications regulation of genomic imprinting and
modulation od miRNA regulation.
play a significant role in the immune system, mainly mediated by protein
binding, and lncRNAs specifically target the nuclear factor-kB (NF-kB) and
signal transducer and activator of transcription 3 (STAT3). Guttman et al. 2009
suggested a role for lncRNAs in the innate immune system in which lncRNAs are
differentially expressed following the activation of monocytes, macrophages, dendritic
cells, 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.
THRIL is found to regulate TNFa (tumour necrosis factor alpha), which is a cell
signalling protein/ cytokine. THRIL has been shown to induce the expression of
multiple inflammatory genes such as IL6 (Heward and Lindsay, 2014). Transcriptomic
and gene knockdown studies revealed that THRIL (previous known as? linc1992),
was critical in the expression of several immune related genes including
cytokines and transcriptional and post-transcriptional regulators of TNFa (li
et al, 2013). There has also been some
clinical significant concerning THRIL, in which it is associated with several
inflammatory diseases such as inflammatory bowel and rheumatoid arthritis, as
well as some associations with the childhood disease Kawasaki disease.
pseudogene has also shown to be induced follow exposure to two genes IL-1? and
GR agonist (ref),
and can also block NF-kB- DNA binding and can inhibit the inflammatory response
to TNF? and IL-1? (Heward and Lindsay, 2014). Lethe dysregulation can play a
role in several immune diseases, especially hyperglycemia where there in an
induced ROS production. Zgheib et al. have indicated that Lethe is involved in
the regulation of ROS production, Lethe controls the regulation of ROS through
the control of NOX2 gene expression via NFkB signalling.
been shown to mediate the induction and repression of gene expression in mouse
macrophages, the lincRNA-Cox2 complex can induce the expression of
approximately 700 genes, which are involved in the immune response including
IL6 and CcL5. Until recently, the function of lincRNA-Cox2 was massively under
described, but whole- transcriptome profiling revealed both an activating and
repressing behaviour of immune genes by lincRNA-Cox2 (Capenter et al., 2013).
limited studies on the roles of miRNAs in the immune system, although there are
some previous studies, which have extensively explored the roles of noncoding
RNAs in the immune system, such as miR-155 functioning as an oncogene, and
miR-155 is also triggered/ upregulated in response to toll like receptor (TLR)
been hypothesised to play a significant role in the development of chronic
lymphocytic leukaemia (CLL), miR-155 levels in patients with CLL increases as B
cells progress to monoclonal B-cell lymphocytosis (MBL) to CLL (Ferrajoli et
al., 2013), there is also an significant expression of miR-155 in the plasma of
patients after treatment shown in Ferrajoli et al 2013. miR-155 expression
represents a good biomarker for CLL, due to the high level gene expression
control it has over B cells.
receptors (TLR), are key in the innate immune system, they can recognise
pathogens and active immune response such as the inflammatory response, resulting
cytokine production and destruction of the pathogenic cell. The receptors are
expressed on the membrane on most cells including dendritic cells, macrophages
and natural killer cells, because of the extreme response of these cells they
require tight control. It is becoming more evident that some miRNAs are
responsible for regulating the expression of TLRs.
based technologies can be used to identify miRNAs which are induced in
macrophages after exposure to cytokines (O’Connell et al., 2006), miRNA-155 has
been shown to be induced following exposure to the cytokine IFN-?, as well as
TLR ligands. With this finding it can be assumed that miRNA-155 is a target for
broad range inflammatory mediators, and play a role in stimulating the cytokine
controlled inflammatory response.
RNAs play a significant cellular role and can have great implications on the
immune 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-coding
RNA 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 many
immune functions, lncRNAs can regulate the cytokine TNFa which can cause
inflammatory diseases and can also induce the expression of IL6 ans Ccl6. MicroRNAs
have been shown to play an import role as an oncogene, especially miR-155 which
is associated with the development of chronic lymphocytic leukaemia from monoclonal
B-cell lymphocytosis, and can be used as a marker to diagnose the development
of the diseases as well as track the effectiveness of the treatment. MicroRNAs
also play a role in the inflammatory response, and are induced following cytokine
exposure, because miR-155 can function as an oncogene and is also a target for
inflammatory mediators we must consider if there is any link between cancer and
inflammation mediated by miR-155.