Dr. Alhassan Hussaini Mohammed
VOLUME: 3 ISSUE: 1
Dr. Alhassan Hussaini Mohammed
ALHASSAN Hussaini Mohammed (PhD)1,2, ALI-AKBAR Saboor-Yaraghi (PhD)2
1. Department of Immunology, Faculty of Medical Laboratory Sciences. Usmanu Danfodiyo University, Sokoto - Nigeria.
2. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, International Campus. TUMS-IC, Tehran- Iran.
Alhassan Hussaini Mohammed, The Differentiation and Roles of inflammatory Cytokine in the initiation of Inflammatory Bowel Diseases (IBD)(2021)Journal of Advances In Allergy & Immunologic Diseases 3(1)
The activation, proliferation and differentiation of naive T-cells are essentially significant in the productions of inflammatory cytokines and maintenance of immune homeostasis and development of various forms of inflammatory disorders. This activation and ultimate differentiation of this group of cells is brought about by the presence of an antigen and other inflammatory mediators in the micro-environment. Inflammatory cytokines like, IL-12 and IL-4 are of great significance in the resultant differentiation of these cells into various subsets, such as, the Th1, Th2, Th17 and T-regs, each of these subsets has a pattern and a specific cytokine profile, an imbalance in this profile may lead to the development of inflammation or other undesirable inflammatory responses, such as observed in inflammatory bowel diseases (IBD).
Crohn’s disease (CD) is a T helper-1-derived autoimmune disease while Ulcerative colitis (UC) are viewed as a T-helper 2-mediated inflammatory condition. Based on the role of this cytokine, they are categorized into pro-inflammatory and antiinflammatory cytokines. The pro-inflammatory cytokines, such as IL-12, IL-2, IL-17, IL-6, TNF-αand INF-γ are responsible for various forms of inflammatory responses. The aim of this review is to look into current research information about Naive T-cells proliferation and the roles of inflammatory cytokine in the initiation and development of inflammatory bowel diseases. Concrete understanding of the functional proliferation and development of this cells may contribute to finding reliable therapeutic modalities for the treatment of inflammatory bowel diseases.
Keywords: Naive-T cell, Ulcerative Colitis, Crohn’s Diseases, cytokines, Dendritic cell
Inflammatory bowel disease (IBD) is an inflammation of the bowel which can be idiopathic and chronic. The aetiologic origins of IBD are yet to be fully understood, but available research report has attributed its emergence to genetic susceptibility, immune dysregulations, environmental factors or bacterial infections . IBD is categorized into two major forms: Ulcerative colitis (UC) and Crohn’s disease (CD), each of this type has its own distinguishing characteristic, but generally, the development of UC and CD are characterised by Neutrophil recruitment, activation and infiltration of intestinal innate immune responses .
Both in children and adults, IBD is recognized as an important cause of gastrointestinal disorders. The disease has a worldwide occurrence, but it is more common in the industrialized nations such as the United States, United Kingdom, and Scandinavian countries than in the developing countries. The prevalence rates of IBD are between 40 to 100/ 100,000 persons , about 20% of all patients with IBD develop symptoms during childhood, with approximately, 6% being diagnosed before 10 years of life, 25% of children affected with IBD have a positive family history of IBD.IBD is of major types, Ulcerative colitis and Crohn’s diseases .
Ulcerative colitis (UC) is an inflammatory disorder in which the morphological changes are restricted to the colon , while in Crohn’s disease (CD), the changes may extend from the oesophagus to the anus, it may transcend all the length of the gastrointestinal tract, but the ileocecal region and the terminal ileum are the most commonly affected location .
ACTIVATION AND DIFFERENTIATION OF NAÏVE T-CELLS
The most important event in the differentiation of naive T-cells, is antigenic stimulation, which as a result of the interaction of CD4+ T-cells and T-cells receptor (TCR) with the major histocompatibility antigen complex II (MHC II), by an antigen presenting cells (APCs). The coupling of CD3 with TCR induces signal transduction, that activates naive-T-cells differentiation into effector and regulatory T-cells . The predominant classes of cytokines produce depend on, the types and presence of inducing cytokines, the concentration of antigens, and type of APCs, and co-stimulatory molecules .
Dendritic cells (DCs) are a type of APCs, that has a high degree of potency in naive T cell sensitization . This is done through the pattern recognition receptors, such as the toll-like receptors (TLR) and nucleotide oligomerization domain-like receptors (NOD) present on the cell surface . There are various subsets of DCs, which can interfere in the proliferations of T-cell, for instance, in mice, CD8α+ DC was linked with a Th1 subset in the presence of IL-12, while the CD8α− subsets were linked to Th2 differentiation, under the influence of IL-6. When dendritic cells are activated, direct stimulatory signals are sent to naive T-cells, which causes its Differentiation in effector T-cells and regulatory T-cells . Both the effector and regulatory T-cells undergo further differentiation to form Th1, Th2, Th17 and ITreg. The balance between Th1/Th17 and Th2/Tregs is significant in the initiation and development of IBD 
THE DIFFERENTIATION OF NAÏVE T-CELLS TO TH1 SUBSETS.
The differentiation of Naive T-cell to Th1 is highly depended on the presence of interferon gamma (IFN-γ) and interleukin 12(IL-12). An exaggerated production of the Th1-derived cytokines which are mainly pro-inflammatory in action could leads to an undesirable inflammatory response, which may bring about the development of various forms of autoimmune diseases, such as IBD . Large amounts of IL-12 are secreted by APCs after their initial activation by an antigen, through the pattern recognition receptors present on the cell surface [9,10] and this is followed by natural killer cells (NK) induction by IL-12 to produce IFN-γ. Th1 differentiation is regulated by the master regulator, T-bet transcription factor (T-box). T-bet possesses the ability to suppress and down-regulates the development of other T-cell subsets, such as Th2 and Th17, while facilitating IFNγ production .
RORγt in mouse and RORc in human is the principal transcription factor of Th17, the Th17 inhibition is brought about by the constant interaction of T-bet with race promoter, which encodes RORγt . The inhibition of Th2 by T-bet is initiated by constant and frequent suppression of IL-4 transcription gene, obstructing the activity of GATA3. IFNγ production can be induce by STAT4, creating a positive feedback mechanism for T-bet and IL12Rβ2 expression. T-bet and STAT4 are directly involved in locus transcription of IFNγ, while GATA3 and STAT6, involvement in Th2 differentiation formed repressive histone marks at IFN-γ locus, this is an indication that Th1 differentiation is determined by the activation of IFNγ locus . Research findings have reported the role of T-bet’s as a repressor of transcription, this is by Bcl-6, a transcriptional repressor induction, which suppresses the effects of IFNγ locus of Th1 proliferation in secondary responses, this may functions as a protective model aimed at inhibiting IBD Immunopathogenesis by downregulating aberrant production of IFNγ .
THE DIFFERATION OF NAIVE T-CELLS TO TH2 SUBSETS
The Naive T-cells differentiation to Th2 subsets depends majorly on the presence of IL-4 and IL-2. STAT6 is induced by IL-4, which is an essential transcription factor in the differentiation of Th2 cell. Gata3 expression is up-regulated by the IL-4-induced STAT6. Three different postulations that explain these mechanisms of Th2 differentiation are:
These mechanisms suppress Th1 differentiation by downregulating STAT4 and inhibition of GATA3 leads to the blockage of Th2 differentiation . Studies have shown that GATA3 needed the assistance of STAT6 to control all the Th2-specific genes [20}, besides GATA3, Th2 cell differentiation involves several other cytokines, such as IL-2, IL-6, and IL-21.
The activation of signal transducer and activator of transcription-5 (STAT-5) is purely independent on IL-4 but dependent on IL-2 signalling . Since GATA3 cannot activate all Th2-specific genes, a synergistic action of STAT5 and GATA3 is required, alone GATA3 cannot cause the production of IL4, this is because GATA3 and STAT5 selectively bind to different epitopes on the IL4 locus. GATA-3 binds to DNaseI hypersensitive site VA and CNS-1 sites of the IL4/IL13 loci and STAT5 binds to the DNase I hypersensitive sites (HSII and HSIII) on the second intron of the IL4 locus and .
In Th2 differentiation, IL6 has a dual function. It enhances Th2 differentiation, while on the other hands, inhibiting the Th1 production . IL-6 also induces IL-4 production by naive T-cells, through the upregulation of nuclear factor of the activated T cells (NFAT). The downregulation of the Th1 differentiation occurs by the IL-6-induced upregulation of suppressor of cytokine signaling-1 (SOCS1) expression, which inhibits STAT1 activation, reducing IFN-γ signalling .
THE DIFFERENTIATION OF NAÏVE T-CELLS TO Th-17
The definition of Th17 majorly relies on TGF-β, IL-6, IL-21, and IL-23, with the participation of the master regulator, Retinoid-related orphan receptor gamma-T (RORγt). The Naïve T-cells differentiation to Th17 has three main components, these are:
The transforming growth factor-β (TGF-β) is one of the most important and principal cytokines in Th17 differentiation . It is signalling plays important roles in inducible T-regulatory cells(I-Treg) development. I-Treg and Th17 are an antagonist in their mode of action to one another. At higher concentration TGF-β can divert the differentiation of Naive T-cells towards ITreg development, through FOXP3 induction , but under the influence of IL-6, and at a lower concentration, TGF-β initiates Th17 definition, up-regulations of IL23R expression, and IL-21 production. Suppression of TGF-β signalling pathway in the presence of IL6 leads to the activation of RORγt .
THE DIFFERENTIATION OF NAÏVE T-CELLS TO REGULATORY T CELLS
The TGF-β is responsible for the initiation of Inducible T-regs (ITreg) . I-Treg cells are FOXP3+CD4+CD25+cells, that develop in the peripheral lymphoid organs after priming with antigen, unlike natural Treg (nTreg), which are released from the thymus as a separate line from an already expressed FOXP3 . TGF-β is a critical cytokine responsible for initiation of adherence to iTreg cell lines. The Forkhead transcription factor, FOXP3 is specifically expressed in CD4 + CD25 + Treg cells and is a major factor involved in iTreg differentiation .
FOXP3, and other transcription factors, such as Smad2 and Smad3, which are also activated via the TGF-signalling pathways, are involved in the iTreg differentiation . Smad3 can differentiate the development of iTreg by enhancing the regulation of FOXP3 expression and inhibiting Th17 differentiation by blocking RORγT. NFAT through interaction with FOXP3 contributed to the differentiation of Th17 . It was found that STAT5 enhances the expression of FOXP3, and then proceeds to signal transduction of FOXP3 and promotes the development of iTreg . STAT5 and STAT3, which communicate with several common sites in the IL17 locus, closely antagonizd each other. Activation of STAT5 by the IL2 signal blocked the binding of STAT3 to the sites on the locus and, consequently, enhances the differentiation of iTreg . The disruption of the interaction of the mutated FOXP3 gene and NFAT resulted in a decrease in the expression of Treg-CTLA4 and CD25 markers 
INFLAMMATORY CYTOKINES AND IBD PATHOGENESIS
ROLE OF IL-12
The IL-12 superfamily is made up of IL-12, IL-23, IL-27 and IL-35. IL-12 and IL-23 are produced by antigen-presenting cells, mainly, dendritic cells and phagocytes [31,32]. Up-regulation of IL-12 expression was seen in the mucosa of patients with UC, and it correlated with the activity of the disease . Research has shown that, in macrophages and mucosal immunity, the basic protein of leucine zipper, NFIL3, is the regulator of IL-12p40 . The interaction of macrophages with the microflora of the colon induced NFIL3 to down -regulate their inflammatory ability. IL-23 facilitates the proliferation and differentiation of naive CD4+T cells into Th17 cells , It is found and widely distributed in virtually all the immune cells as its expressed by CD4+T cells, CD8+T cells, NKT cells, and NK cells, . IL-23 plays a pro-inflammatory role in colitis, which is mediated by T-cells, caused by 2,4,6-trinitrobenzenesulfonic acid (TNBS), IL-23 can also be termed to have an anti-inflammatory function because it suppresses production of IL-12 . The signalling of IL-23 occurs mainly through the transition molecule STAT3. IL-23 also facilitates the proliferation of naive T-cells into regulatory T cells (Tregs) .
IL-12 expression is increased in the mucosa of patients with active Crohn (CD) , and due to the up-regulation of the levels of IL-12p40 and IL-12Rβ2 in the primary phase of CD initiation, it is said that IL-12 may participate in the early induction of Th1 -polarization of naive T-cells . IL-12- dependent synthesis of IFN-γ of mucosal T cells can be facilitated by cytokines that feed the signal through a common γ-chain receptor . IL-23 has an elevated level of mucosa in Crohn's disease . The production of IL-17 and IL-6 appears to mediate IL-23-induced inflammation of the intestine .
IL-27 is described as a heterodimeric novel member of the IL-12 family. In in-vitro studies, it was shown that IL-27 is produced by the presence of activated dendritic cells and monocytes, which initiates the proliferation of naive CD4+T cells and co-ordinates with IL-12 for IFN-γ production .
ROLE OF TNF-α
The family of TNF comprises of 18-type 2-protein molecules which occur either as a membrane bound or soluble form, their receptors are transmembrane proteins type 1 . The receptor binding of TNF-like ligands triggers intracellular responses that are involved in the proliferation and differentiation and ultimate survival of the cells. TNF-α is the main and master cytokine in the pathogenesis of IBD . It manifests its effects by the secretion of adhesion molecules, the proliferation of fibroblasts, and pro-coagulant factors, more-so through the initiation of cytotoxic, apoptotic and acute phase reactions . These basic cytokines have the ability to increase the production of IL-1β, IL-6 and IL-33, and also modulate the expression of ST2 in epithelial cells .
Serum TNF-α levels correlated with ulcerative colitis (UC) and CD clinical activity . Their roles in inflammation of the colon were the basis for the anti-TNF-α antibodies therapy in IBD. The tumor necrosis factor (TL1A), is another TNF family member, it stimulates the secretion of IFN-γ by binding to the death receptor 3 (DR3) . Binding of TNF-α to the soluble TNF receptor 1 and 2 (sTNFR1 and 2) results in the initiation of inflammatory responses .
In CD patients, the levels of sTNFR1 and 2 are elevated when compared to UC and healthy controls, so it can be used as a biomarker for disease activity and a discriminatory factor between Ulcerative colitis and Crohn’s diseases . The pro-inflammatory role of TNF-α has confirmed the use of antibodies against TNF-α in the treatment of CD . Another important TNF family member is called the Light, it mediated pro-inflammatory activity in the human intestinal mucosa, and It was reported that in CD the IFN producing CD4 + T cells expresses LIGHT as a mediating Th1 response 
The roles of IL-17
IL-17 is produced by Th17 cells, it acts as a key mediator in increasing the production of chemokines and in the recruitment of monocytes and neutrophils in the inflammatory responses. IL-17A is Th17 cells, but in chronic inflammation, this cytokine is also produced by CD8+ T cells . It was shown that IL-25 has a strong capacity to inhibit CD14+cell-derived cytokines, specifically, IL-12 production and experimental colitis caused by Th1 cells, which indicates its therapeutic potential in CD and UC .
The mucosal level of IL-17 in human is significantly increased in active CD also studies has also reported that, the level of circulating memory cells of CD161+cells, IL-17 and IFN-γ increases in patients with CD, . More-so, there is an increased level of circulating IL-23R expressing T cells in patients with CD that respond to IL-23 with increased production of IL-17, IL-22 and IFN-γ, this is also enhanced by the presence of IL-1β . In line with research findings, it was concluded that Th17 cells, producing both IL-17 and IFN-γ are identified as important effector cells in the inflammatory response in CD.
The production of IL-21 is significantly increased in the mucosa of CD . IL-21 is produced exclusively by T-cells that produce CD4 + IFN-γ, but only a little proportion of IL-21 produces CD4+ T cells expressing IL-17A, which indicates that IL-21 is mainly produced by Th1, rather than Th17 subsets. Stimulation of CD4 + T-lymphocytes from the control GIT with an anti-CD3 antibody and IL-12 increases the number of IL-21-secreting Th1 cells. While the blockade of endogenous IL-12 in cell cultures of CD mucosa significantly reduces the percentage of IL-21 production .
Roles of IL-1
The IL-1 family has two structurally different forms: IL-1α and IL-1β. The endogenous IL-1 receptor antagonist (IL-1Ra) is a natural antagonist of IL-1, which maintain a healthy balance of immunity in the GIT . An increase in the ratio of IL-1 / IL-1Ra is related to increase in disease activities in ulcerative colitis. IL-33 also known as IL-F11, has been identified as another the new family member of the IL-1 . It involved is in allergy, inflammation of the respiratory tract and rheumatic diseases . Schmitz et al., reported that IL-33 apparently, restores the protective barriers of the mucosa by increasing mucus secretion and enhancing the immune response through cytokines associated with type 2 helper T-cells (Th2) . It has been shown that the expression of the IL-33 receptor, ST2, increases both in the wall of the colon and in the serum of patients with IBD . In the large intestine, the axis of IL-33 / ST2 may have multiple functions in inflammatory bowel disease (IBD) pathogenesis. Stimuli of cytokines, such as TNF-α and IL-1β, and Immune responses from the pathogen-associated molecular pattern (PAMP) could result to up-regulation in the level of IL-33 in epithelial cells. In the case of epithelial damage, IL-33 is released from cells and facilitates immune responses via ST2, which expresses immune cells, this leads to an increase in the severity of the inflammation .
The proportional up-regulation of IL-1 / IL-1Ra is related to increase in flare in CD activities . IL-18 is a member of the IL-1 family , In the inflamed mucosa of patients with CD, the level of IL-18 is up-regulated . The balance between the proinflammatory cytokine and the IL-18 binding protein (IL-18BP), which is its natural inhibitor, has a huge contribution to the pathogenesis of IBD . It has been reported by Leach et al., that IL-18, produced in the colon of patients with CD especially that in children, contributes significantly to local inflammatory responses and changes .
Roles of IL-6
The IL-6, IL-11, IL-31 are members of the IL-6 family. Circulating levels of IL-6 and sIL-6R correlate with disease activity  The pathogenic role of the IL-6 and sIL-6R signalling in interfering with T-cell resistance to CD apoptosis was confirmed by blocking IL-6 trans-signalling . These research findings have shown that IL-6 can influence not only the chronic inflammatory pathways, but also the relapses that arise in the pathology of CD. The effects of IL-6 in IBD were demonstrated in Caco2 cells, where it was shown that IL-6 induces the activation of NF-kappa β and enhances the expression of intercellular adhesion 1 molecule. This adhesion molecule is important in the pathogenesis of IBD and is most likely required for the extra-intestinal manifestation of IBD . All the available research data have suggested that blockade of the IL-6 / STAT3 signalling pathways and the use of antibodies against IL-6R have been suggested as a new and promising therapeutic strategy in the treatment of IBD .
Role of IL-8
IL-8 has been described as a heparin-binding small base protein, which belongs to the cysteine amino acid cysteine chemokine . The activation, movement and neutrophilic migration in peripheral blood are primarily mediated by IL-8. Studies have shown that, in active UC, the level of tissue IL-8 was higher compared to normal tissue, more-so, its concentration in the serum was associated with the severity of UC.
Roles of IL-13
IL-13 is a Th2-derived cytokine, important in the development and manifestation of UC . Expression of IL-13 mRNA in the mucosa of UC is increased and also, the ex vivo culture of LPMC from UC shows appreciable amounts of IL-13 during stimulation than that obtained from healthy and CD patients . UC-specific CD161+NKT cells have a cytotoxic response against colon epithelium, whose effect, at least in part, depends on functional IL-13. Subsequent responses, such as the NKT cell cytotoxic activity, induced apoptosis of epithelial cells by IL-13, and disruption of dense compounds all constitute into an epithelial damage . It has also been recently shown that IL-13 signalling through IL-13Rα2 leads to an increase in the production of the transforming growth factor (TGF) -β1, which favours the progression of colonic wall fibrosis .
Roles of IL-5 AND IL-21
IL-5 is a selective eosinophil-activating hormone, it is also referred to as an eosinophil differentiation factor. IL-5 belongs to the family member of common β-chain-dependent cytokine. A higher amount of IL-5 is produced in mononuclear cells in active UC, but not in CD . IL-5 appears to play a regulatory role in the regeneration of eosinophils in the mucosa of UC .
IL-21 is a T-cell derived member of common γ-chain-dependent cytokine family, it acts to maintain Th1-mediated inflammation in the colon epithelium, inducing the production of IFN-γ . The number of IL-21 cells is much higher in CD than seen in UC . Research has also indicated that IL-21 enhances the expansion of NK cells . It is expressed by immune T-and B-cells and non-immune cells, such as fibroblasts, where it activates the production of metalloproteinase 1 and transmits signals through its IL-21R receptor, it activates STAT-3 in T cells . IL-21, like IL- 6 and IL-23, also participates in the proliferation of Th17 cells and is overexpressed in both CD and UC, with higher levels found in CD .
IBD is the result of an aberrant immunological response of Naive T–cells to exaggerated antigenic stimulation, which leads to a dysregulated immune response. The result of this review has shown that inflammatory cytokine is not only related to the maintenance of the immune haemostasis but are also concerned with protections against foreign invasion. So concerted research effort should be directed at understanding the immunological and signalling pathways and the exact mechanisms that are involved in the initiation of exaggerated immune responses. Understanding the immunological pathways underlying the pathogenesis will not only assist in the treatment of IBD but will also help in alleviating the burden of very many other inflammatory disorders and autoimmune diseases.
I wish to express my sincere appreciation to the management of Tehran University of Medical Sciences, Management of TUMS-International Campus, for providing me with an enabling environment and making available their facilities for this review.
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