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The immune system of an organism is capable of mounting a variable number of immune responses to foreign elements. The scale and extent of this response needs to be regulated at various levels. The cells of the immune system like macrophages, dendritic cells and T cells, mediate these responses under the regulatory control of cytokines. Cytokines are important factors that determine cell differentiation, growth and function. Interleukins, interferons and hematopoietic growth factors are some of the cytokines that activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. To regulate the way the cells respond to cytokines, certain proteins called suppressors of cytokine signalling (SOCS) are essential.
SOCS proteins are proven to be induced by a number of stimuli, mainly cytokines. This elucidates the negative feedback loop system that may be the mechanism used in SOCS-mediated cytokine signalling.
SOCS Structure and Function:
SOCS proteins together with cytokine-inducible SRC homology 2 (SH2)-domain containing proteins (CIS) form an 8-member family of intracellular regulatory proteins (CIS and SOCS1-SOCS7). Their structure is characterised by a central SH2 domain, an amino terminal variable length domain and a 40 amino-acid carboxy terminal module called the SOCS box.
The regulatory action of SOCS proteins is mediated by two main mechanisms- ubiquitin-mediated degradation, involving binding activity of the SOCS box; and inhibition of JAK tyrosine kinase through their kinase inhibitory region (KIR), which together with tyrosine kinase inhibitor peptide (TKIP) have shown to impede JAK-2 mediated phosphorylation of STAT1. Target recognition of SOCS proteins is dependent on the central SH2 domain, which bind differently for different SOCS proteins. Certain proteins like SOCS1 may also bind directly to cytokine receptor; however experimental evidence proves effective inhibition of interferon gamma (IFNγ) when the direct binding of SOCS1 is followed by phophorylation of tyrosine residue on IFN receptor.
SOCS proteins and innate immunity:
Toll-like receptors (TLRs) involved in innate immunity bind to ligands and trigger immune responses like inflammation against pathogens. These ligands, such as lipopolysaccharides (LPS) and CpG-containing (GC rich) DNA, also induce SOCS1 andSOCS2, revealing their role in TLR responses. Absence of SOCS regulation leads to over-production of tumour necrosis factor (TNF), IFNγ and interleukin (IL)-12 due to increased hypersensitivity to LPS, as studied in SOCS1-deficient mice. The efficient suppression of cytokines is effected by several mechanisms. These include binding and subsequent ubiquitin-mediated degradation of p65 subunit of NF-κβ (nuclear factor -κβ); binding and ubiquitin-mediated degradation of MAL (myeloid differentiation primary response gene88 (MyD88)-adaptor-like-protein); inhibition of the JAK-STAT pathway, etc. SOCS1 represses the expression of CD40 gene, which is caused by NF-κβ and JAK-STAT1; the JAK-STAT1 being activated by IFNβ. This is induced by TIR (Toll/IL-1R) domain-containing adaptor protein inducing IFNγ (TRIF)-IFN-regulatory factor 3 (IRF3) pathway. SOCS1 is thus a negative regulator of JAK-STAT and TLR pathway, which are involved in maturity of inflammatory bowel diseases.
Apart from SOCS1, SOCS3 also plays a crucial role in TLR signalling. The two cytokines having opposing function that are activated post TLR stimulation are IL-6 (pro-inflammatory cytokine) and IL-10 (immunoregulatory cytokine). Both of them together with LPS induce SOCS3; however binding of SOCS3 to IL-6 receptor subunit selectively inhibits IL-6, while IL-10 is unaffected. STAT3 also functionally activates these two cytokines, however its sustained activation is necessary only for anti-inflammatory action (IL-10 mediated) while transitory activation promotes inflammation (IL-6 mediated). It is hypothesized that there is suppression of anti-inflammatory genes by the IL-6 receptor and SOCS3, even in the presence of STAT3. The other kinds of mechanisms by which TLR signals are suppressed include cytokine-independent activation of STAT3 (employed during microbial evasion of host-immune responses) and acetylcholine receptor mediated activation of STAT3.
SOCS proteins and dendritic cell (DC) activation:
DCs are effective antigen processing and antigen presenting cells that are responsible for the development and activation of various lymphocytes. These cells play a crucial role in the divergence of the TH1 and TH2 subset from the T-helper cells (TH), which is effected by the differential cytokine profile of DCs. For e.g. IL-12 promotes TH1-cell differentiation, while TGFβ and IL-6 and/or IL-23 are involved in differentiation of TH17-cell differentiation. SOCS proteins intricately regulate DC activation.
SOCS proteins are involved in TLR inhibition of GM-CSF (granulocyte/macrophage colony stimulating factor)-mediated DC development. The up-regulation of STAT1 is considered to be involved in his process. Maturation of DCs causes the STAT6 signalling pathway to be converted into the STAT1 pathway, a process attributed to high levels of SOCS1 expression. The SOCS1 deficiency-induced systemic autoimmunity in combination with small-interfering RNA (siRNA) technology is being evaluated as vaccination against HIV (human immunodeficiency virus).
SOCS3-transduced DCs express higher levels of IL-10 and low levels of IL-12, IFNγ and IL-23, thereby causing induction of TH2-cell differentiation, thus making clear the significance of SOCS3 in maintaining the balance between effector TH2cells and regulatory T cells.
SOCS proteins and infection:
Inhibition of IFN signalling by SOCS1 is involved in maintaining a balance between beneficial antiviral and harmful pro-inflammatory effects of IFN signalling. Experimental analysis has proved the importance of SOCS1 proteins in host defence against viral infection. This is achieved by regulating the sensitivity of tissue cells to IFN. SOCS1 also functions in the resistance against non-viral infectious agents and intracellular parasites. Deficiency of SOCS1 causes hypersensitivity to IFN and imparts resistance. Thus the negative effect of SOCS1 on IFN is used as an evasion strategy by parasites. SOCS3 is also involved in infection, though it mediates its action via a mechanism different from SOCS1. It causes cytolysis by impairing STAT3, which prevents cellular breakdown caused by viral infection.
SOCS proteins in early T cell development and differentiation:
SOCS1 proteins are abundantly expressed in double positive T cells (DP; CD+CD8+); these cells need pro-survival cytokines (e.g. IL-7) for their survival. Experimental data proves that high levels of expression of SOCS1 make the T cells insensitive to pro-survival signals so as to prevent any involuntary signalling. IFNγ can interfere with the normal development of CD4+ and CD8+ lineages and therefore SOCS1 protein regulate their level and prevent any harmful development in the cell.
Study on SOCS1-deficient mice has revealed the role played by IL-15 in development of memory in peripheral CD8+ T cells even in the absence of antigenic stimulation. This is detrimental to the cell. The IL-15 induced hyperactivation of CD8+ cells is thus regulated by SOCS1 proteins. SOCS1 proteins also prevent any undesirable proliferation of self-reactive CD8+ T cells, thus averting diseases like autoimmune diabetes.
SOCS proteins also play a regulatory role in TH differentiation into TH1 and TH2 subsets. It has been proved through various experiments that SOCS1 expression is found higher in TH1 cells and SOCS3 is found abundantly elevated is TH2 cells. This action is caused by negative regulation of the cytokines involved in development of the opposite subset. For e.g. SOCS3 inhibits action of IL-12, which is necessary for TH1 differentiation; thereby enhancing TH2 proliferation. SOCS1 interferes with activity of IFNγ and IL-4, elucidating the role it plays in mutual inhibition of TH1 and TH2 cells.
CD4+ TH cells that produce IL-17 are called TH17 cells and their differentiation is effected by TGFβ, IL-23 and IL-6; while they are inhibited by IFNγ and IL-4. This inhibition is only effective in naive CD4+ T cells as mature TH17 cells show resistance to IFNγ action. This defiance of committed TH17 can be due to high levels of SOCS1 in them, which inhibits IFNγ activity. SOCS3 shows negative regulation of IL-23 and IL-6, thereby suppressing STAT3 activation and TH17 cell development. IL-27, a member of the IL-6/IL-12 family also exerts inhibitory action on TH17 cell development in an IFNγ and SOCS3-independent mechanism. Thus the dependence of the fine regulation of TH cell balance on SOCS and STAT proteins can be well comprehended.
TGFβ is a potent inducer of regulatory T cells (Treg), which express FOXP3. TH3 cells are a subset of Treg expressing high levels of TGFβ and induced by IL-4, IL-10 and TGFβ. IL-2 suppresses Treg cells. SOCS1 promotes the survival and/or proliferation of Treg cells by inhibiting IL-2.
SOCS proteins and human diseases:
A number of human diseases have been associated to increased or decreased levels of SOCS proteins. Asthma pathogenesis has been attributed to single nuclear polymorphisms in SOCS1 and increased SOCS3 levels. Silencing by DNA hypermethylation, caused by SOCS1 gene deletion and mutation, results in lymphoma and myelodysplastic syndrome. Lower levels of SOCS1 and other viral proteins cause constitutive activation of JAK-STAT pathway resulting in cell proliferation and diseases like hepatocellular carcinomas and colitis-induced colon tumours. Decreased levels of SOCS1 protein followed by increase in STAT1 expression increases susceptibility to tissue-injury and inflammation. Thus the anti-oncogenic effect of SOCS1 prevents carcinogenesis.
Higher levels of SOCS3 are detected in hepatitis C viral infection; whereas decreased levels may be associated to constitutive STAT3 activation contributing to tumorigenesis in various human cancer cells.
SOCS proteins and therapeutics:
Control of inflammatory diseases by inhibiting cytokine signalling can be brought about by over-expressing SOCS protein. This can be incorporated as a therapeutic measure by adenovirus-mediated overexpression; using small-molecule mimetics of SOCS proteins; etc. Thus modulation of SOCS levels, based on an understanding of its varied actions, can be effectively integrated for therapeutic applications.
A decade has passed since the discovery of SOCS proteins and a lot of mechanisms have been understood and researched upon. However, a huge spectrum of aspects still awaits discovery. Mathematical understanding and development of simulation models can play a major role in drug discovery and design. The effect of SOCS proteins on other immune cells yet needs to be clearly illustrated. Details of pathways involved during SOCS action are yet to be researched upon, making SOCS proteins an interesting and exciting field of investigation.
Research has been carried out to evaluate the effect of SOCS proteins on neuronal growth and differentiation (neuritogenesis)1. SOCS6, a lesser-known member of the CIS-SOCS family of proteins, differs from the rest of the SOCS proteins because of the presence of a 300 amino acid extension at its N-terminal. Elevated levels of this protein have been shown to exist during cell differentiation in neuronal stem cells, at the protein as well as mRNA level. Over-expression of SOCS6 has been found to increase neurite outgrowth and degree of branching. Neurite initiation and extension has been shown to be negatively affected in cell lines in which SOCS6 was knocked down using siRNA technology. Bioinformatics analysis has revealed involvement of transcription factors STAT5a and STAT5b in upregulation of SOCS6 gene leading to neuronal differentiation. Post-differentiation, SOCS6 has been shown to form a ternary complex with Insulin-Like Growth Factor-1 Receptor (IGFR) and JAK2. The pathway thus affected has been investigated as the JAK-STAT pathway.
Further study of different members of the CIS-SOCS family as well as the mechanisms and pathways by which they mediate their action can provide an informational framework on which various drugs can be designed. The involvement of SOCS proteins in tumorigenesis reveals their importance in therapeutics and research. A thorough understanding of the various other factors that affect protein expression can provide the foundation for breakthroughs in drug design.