Cytokines In Inflammatory Bowel Disease Research Articles

Protective effects of Moringa oleifera against acetic acid-induced colitis in rat: Inflammatory mediators’ inhibition and preservation the colon morphohistology

Moringa oleifera decoction is used in folk medicine to alleviate various gastrointestinal ailments and has been shown in several studies to exhibit diverse biological activities: antioxidant, anti-inflammatory, and myorelaxant on intestine strips. However, its protective effect on pro-inflammatory cytokines in colitis remains to be ascertained. We investigated Moringa oleifera leaf aqueous extract activities on a rat model of acetic acid-induced colitis. Thirty-six rats were divided in random into six groups, and received either distilled water (10 mL/kg), the aqueous leaf extract of Moringa oleifera (25, 50, and 100 mg/kg) or the reference drug Loperamide (5 mg/kg) for 20 days. Animal body weight and food intake were followed-up. Colitis was induced on day 15, and daily stool weight was followed up. Animals were sacrificed (day 21), serum concentrations of pro-inflammatory cytokines MPO, IL-6, and TNF-α were evaluated, and the colon and liver preserved for histological examinations. After one-week pre-treatment, a significant (P < 0.05) weight increase was observed. At day 20, the extract significantly (P < 0.01) prevented weight loss. Food intake decreased by 36.33% in the colitis control, and by 4.34% in the extract (100 mg/kg) treated animals (P < 0.01). Moringa oleifera (100 mg/kg, day 20) decreased stool weights to 4.75±0.3 g (P < 0.05). The extract decreased (P < 0.01) MPO level. At 100 mg/kg, it significantly (P < 0.05) reduced IL-6 –0.58 ± 0.14 against 0.85 ± 0.00 ng/L in the colitis control. At the same dose, TNF-α levels decreased to 417.96 ± 0.17 ng/L (P < 0.001). Moringa oleifera alleviated colitis symptoms by reducing stool emission, alleviating inflammation, and preserving colon and liver cytoarchitecture.

Strategies for targeting cytokines in inflammatory bowel disease.

Cytokines produced by immune cells contribute to the development and perpetuation of inflammatory bowel disease (IBD), namely Crohn's disease and ulcerative colitis, by regulating various aspects of the inflammatory response. Pro-inflammatory cytokines trigger chronic intestinal inflammation, tissue damage, carcinogenesis and perpetuation of disease and suppress the resolution of inflammation in IBD. The clinical success of antibodies that neutralize tumour necrosis factor (TNF) and thecytokineIL-12p40 in individuals with IBD has underscored this concept. Moreover, genetic and preclinical studies have emphasized the crucial role of IL-23 in IBD, leading to clinical approval of antibodies targeting this cytokine. Multiple studies have also investigated the administration of cytokines with assumed anti-inflammatory effects, but this approach has yet to show any real clinical benefit in individuals with IBD. Recent studies have targeted the cytokine network through the use of multi-cytokine blockers (for example, Janus kinase (JAK) inhibitors), IL-2-induced regulatory T cells or advanced combination therapies that use multiple cytokine blockers simultaneously (for example, anti-TNF along with anti-IL-23 antibodies). This Review will focus on our current understanding of how cytokines produced by innate and adaptive immune cells contribute to IBD pathogenesis and discuss how their modulation may inform future treatments for IBD.

TH17 cell: a double-edged sword in the development of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the gastrointestinal tract, and its pathogenesis has not been fully understood. Extensive dysregulation of the intestinal mucosal immune system is critical in the development and progression of IBD. T helper (Th) 17 cells have the characteristics of plasticity. They can transdifferentiate into subpopulations with different functions in response to different factors in the surrounding environment, thus taking on different roles in regulating the intestinal immune responses. In this review, we will focus on the plasticity of Th17 cells as well as the function of Th17 cells and their related cytokines in IBD. We will summarize their pathogenic and protective roles in IBD under different conditions, respectively, hoping to further deepen the understanding of the pathological mechanisms underlying IBD and provide insights for future treatment.

Multifaceted role of CD14 in innate immunity and tissue homeostasis

CD14 is a co-receptor of Toll-like receptor (TLR)− 4, with a critical role in innate immune responses. CD14 recognizes bacterial lipopolysaccharides, pathogen-, and damage-associated molecular patterns, thereby facilitating inflammatory immune responses. In addition to its well-established association with TLR4, CD14 is also implicated in TLR4-independent signaling, which leads to the apoptotic death of differentiated dendritic cells and activation of the noncanonical inflammasome pathway. CD14 also has a role beyond that of the immune responses. It contributes to tissue homeostasis by promoting the clearance of various apoptotic cells via recognizing externalized phosphatidylinositol phosphates. CD14 also has context-dependent roles, particularly in barrier tissues that include the skin and gastrointestinal tract. For example, CD14+ dendritic cells in the skin can induce immunostimulatory or immunosuppressive responses. In the gastrointestinal system, CD14 is involved in producing inflammatory cytokines in inflammatory bowel disease and maintaining of intestinal integrity. This review focuses on the multifaceted roles of CD14 in innate immunity and its potential regulatory functions in barrier tissues characterized by rapid cell renewal. By providing insights into the diverse functions of CD14, this review offers potential therapeutic implications for this versatile molecule in immune modulation and tissue homeostasis.

Advances in the study of the pathogenesis of cytokines in inflammatory bowel disease

Advances in the study of the pathogenesis of cytokines in inflammatory bowel disease

Dual function of fungi-derived cytokines in inflammatory bowel diseases: protection or inflammation.

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition involving both the innate and adaptive immune systems. Recently, the role of intestinal fungal flora and their downstream immune pathways has been highlighted in the pathogenesis of IBD. Cytokines as primary immune mediators require a delicate balance for maintaining intestinal homeostasis. Although most cytokines have a predictable role in either amplifying or attenuating inflammation in IBD, a few cytokines have shown a dual function in the inflammatory state of the intestine. Some of these dual-faced cytokines are also involved in mucosal anti-microbial defense pathways, particularly against intestinal fungal residents. Here, we reviewed the role of these cytokines in IBD pathogenesis to achieve a better understanding of the fungal interactions in the development of IBD.

Targeting cytokines in inflammatory bowel disease.

Targeting cytokines in inflammatory bowel disease (IBD) is a useful clinical approach. Potential therapies for IBD include regulatory T cell transfer to restore cytokine balance, blocking proinflammatory cytokines (e.g., IL-12 and IL-23) or their receptors (sIL-6R and IL-36R), or inhibiting signaling kinases (e.g., JAK). An emerging trend in IBD therapy is to combine several anti-cytokine agents simultaneously.

Role of a probiotic strain in the modulation of gut microbiota and cytokines in inflammatory bowel disease

ObjectiveTo assess the effect of a probiotic strain Bacillus clausii UBBC-07 on gut microbiota and cytokines in IBD patients. MethodPatients were randomly allocated to either placebo or probiotic Bacillus clausii UBBC-07 for four weeks along with the standard medical treatment (SMT). Enrolled patients were evaluated before and after intervention for presence of the given probiotic, change in gut microbiota, change in serum cytokines, serotonin and dopamine, symptoms of disease, physical, behavioral and psychological parameters. ResultsProbiotic strain Bacillus clausii UBBC-07 showed good survival in IBD patients in the treatment group (p < 0.01) without any reported adverse event. Metagenomic analysis showed that the given probiotic strain was able to modulate the gut microbiota in treated group. Phylum Firmicutes was increased and phylum Bacteroidetes was decreased in the probiotic treated group. A significant increase was observed in the abundance of anaerobic bacterial genera Lactobacillus, Bifidobacterium and Faecalibacterium in the probiotic treated group (p < 0.01) as compared to placebo group. Significant increase was observed in IL-10 (p < 0.05) and variable decrease in the secretion of IL-1β, TNF- α, IL-6, IL -17 and IL -23 in probiotic treated group. In the treatment group a significant decrease in the symptoms of IBD and improvement in the psychological parameter to various degrees was noted. ConclusionThese results indicated that probiotic strain B clausii UBBC-07 affected the gut microbiota and cytokine secretion and shown efficacy in IBD patients.

New progress in research of Th17 cells and related cytokines in inflammatory bowel disease

New progress in research of Th17 cells and related cytokines in inflammatory bowel disease

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The uncontrolled abnormal intestinal immune responses play important role in eliciting inflammatory bowel disease (IBD), yet the molecular events regulating intestinal inflammation during IBD remain poorly understood. Here, we describe an endogenous, homeostatic pattern that controls inflammatory responses in experimental murine colitis. We show that Spink7 (serine peptidase inhibitor, kazal type 7), the ortholog of human SPINK7, is significantly upregulated in dextran sodium sulfate (DSS)-induced murine colitis model. Spink7-deficient mice showed highly susceptible to experimental colitis characterized by enhanced weight loss, shorter colon length, higher disease activity index and increased colonic tissue destruction. Bone marrow reconstitution experiments demonstrated that expression of Spink7 in the immune compartment makes main contribution to its protective role in colitis. What's more, neutrophils are the primary sources of Spink7 in experimental murine colitis. Loss of Spink7 leads to augmented productions of multiple chemokines and cytokines in colitis. In summary, this study identifies neutrophils-derived endogenous Spink7-mediated control of chemokines/cytokines production as a molecular mechanism contributing to inflammation resolution during colitis.

Neutrophils-derived Spink7 as one safeguard against experimental murine colitis

The uncontrolled abnormal intestinal immune responses play important role in eliciting inflammatory bowel disease (IBD), yet the molecular events regulating intestinal inflammation during IBD remain poorly understood. Here, we describe an endogenous, homeostatic pattern that controls inflammatory responses in experimental murine colitis. We show that Spink7 (serine peptidase inhibitor, kazal type 7), the ortholog of human SPINK7, is significantly upregulated in dextran sodium sulfate (DSS)-induced murine colitis model. Spink7-deficient mice showed highly susceptible to experimental colitis characterized by enhanced weight loss, shorter colon length, higher disease activity index and increased colonic tissue destruction. Bone marrow reconstitution experiments demonstrated that expression of Spink7 in the immune compartment makes main contribution to its protective role in colitis. What's more, neutrophils are the primary sources of Spink7 in experimental murine colitis. Loss of Spink7 leads to augmented productions of multiple chemokines and cytokines in colitis. In summary, this study identifies neutrophils-derived endogenous Spink7-mediated control of chemokines/cytokines production as a molecular mechanism contributing to inflammation resolution during colitis.

Immunomodulatory Effects of Dietary Polyphenols.

Functional and nutraceutical foods provide an alternative way to improve immune function to aid in the management of various diseases. Traditionally, many medicinal products have been derived from natural compounds with healing properties. With the development of research into nutraceuticals, it is becoming apparent that many of the beneficial properties of these compounds are at least partly due to the presence of polyphenols. There is evidence that dietary polyphenols can influence dendritic cells, have an immunomodulatory effect on macrophages, increase proliferation of B cells, T cells and suppress Type 1 T helper (Th1), Th2, Th17 and Th9 cells. Polyphenols reduce inflammation by suppressing the pro-inflammatory cytokines in inflammatory bowel disease by inducing Treg cells in the intestine, inhibition of tumor necrosis factor-alpha (TNF-α) and induction of apoptosis, decreasing DNA damage. Polyphenols have a potential role in prevention/treatment of auto-immune diseases like type 1 diabetes, rheumatoid arthritis and multiple sclerosis by regulating signaling pathways, suppressing inflammation and limiting demyelination. In addition, polyphenols cause immunomodulatory effects against allergic reaction and autoimmune disease by inhibition of autoimmune T cell proliferation and downregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), IL-1, interferon-γ (IFN-γ)). Herein, we summarize the immunomodulatory effects of polyphenols and the underlying mechanisms involved in the stimulation of immune responses.

New therapies for inflammatory bowel diseases

Currently, Inflammatory Bowel Disease (IBD) is considered an immune-mediated disease. The most widely accepted etiopathogenic hypothesis is that it is due to an inadequate interaction between the immune system and the microorganisms that form the normal intestinal flora. This abnormal interaction occurs in genetically predisposed subjects under the influence of various environmental factors (such as tobacco, diet, stress, or recurrent bacterial infections), which could act as triggers for alterations in the intestinal epithelial barrier. This would lead to an increase in the permeability of barrier, allowing the translocation of microbial products to the wall of the digestive tract, which would activate an acute cell-mediated immune response[1]. The failure of the anti-inflammatory regulatory mechanisms, together with an excess in the production of pro-inflammatory cytokines, would promote an aberrant immune response that would be self-perpetuating over time, thus giving rise to the chronic inflammation that characterizes IBD[2]. Since the first descriptions of Ulcerative Colitis (UC) and Crohn's Disease (CD), many treatments have been developed, with varying degrees of safety and efficacy. At the end of the 20th century, the first biological, called Infliximab, began to be used. A biological drug is one that has a biotechnological origin and arises from proteins derived from DNA and hybridization processes, which require living organisms as a fundamental part of the production process[3]. Undoubtedly, the appearance of biologics in the therapeutic arsenal of IBD was a very important advance in the treatment of these patients, a true revolution. Until that date, many of the patients who began to be treated with this biologic could only do with corticosteroids or by surgery. These drugs have been shown to be effective in reducing intestinal damage caused by chronic inflammation, the need for surgery and hospital admissions and, consequently, have improved the quality of life of many patients[4]. The demonstrated benefit of these drugs, especially when administered early, as well as their favorable safety profile, have led to their increasingly frequent use in the treatment of patients with IBD. They can be divided into - anti-TNF drugs (blocking the cytokine TNF-α), - Vedolizumab (blocking the integrin α4β7) and - Ustekinumab (blocking Interleukin 12 and 23). Recently, and only for use in UC, Tofacitinib (an inhibitor of the JAK-kinase pathway) has been approved and has demonstrated its efficacy in the treatment of moderate-severe active UC[5]. The management of all these drugs represents a challenge for the digestive specialist who must know their mechanisms of action and use them appropriately in patients with IBD. Anti-TNF drugs, being the oldest, are the ones with which we have the most experience and, therefore, they are usually used in the first line in those cases in which conventional drugs (corticosteroids and / or immunosuppressants) have failed. There are three currently marketed in Spain: Infliximab (for intravenous administration), Adalimumab (for subcutaneous administration) and Golimumab (for subcutaneous administration). Vedolizumab (administered intravenously), and Ustekinumab (administered subcutaneously, after a first intravenous administration) are characterized by having an excellent safety profile and a very low immunogenic potential compared to anti-TNF drugs. There are many lines of research currently underway to try to identify the clinical factors of the patient that would make one drug or another more useful in the first line. Other lines seek to identify genetic factors (it seems that mutations in the HLA DQA1 * 05 haplotype could increase immunogenicity to anti-TNF drugs[6]) and also molecular factors[7].

Субпопуляции Т-хелперов, ключевые цитокины и хемокины в патогенезе воспалительных заболеваний кишечника (часть 2)*

Studies in recent decades have identified the role of various T-helper cell subsets in the pathogenesis of inflammatory bowel diseases (IBD) and have shown the importance of cytokine-mediated regulation of the immune response in patients with ulcerative colitis (UC) and Crohn’s disease (CD). The imbalance between pro-inflammatory and anti-inflammatory cytokines in IBD prevents resolution of inflammation and leads to chronic course, disease progression and tissue destruction. In the review article, the role of key cytokines that are important in the development and progression of IBD is discussed. Of the pro-inflammatory mediators involved in the pathogenesis of IBD, special attention is currently paid to chemokines – cytokines belonging to chemoattractants. Chemokines are responsible for directed migration and attraction of cells expressing a certain set of receptors to organs, tissues and foci of inflammation. The article provides unique data on the importance of some chemokines in IBD. Cytokines, chemokines and their receptors are considered as potential therapeutic targets in IBD. Cytokine-targeted therapy using antibodies against TNF-α and antibodies to IL-12/IL-23 have already shown high efficiency and safety in randomized clinical trials, as well as in real clinical practice in patients with IBD. The data presented by the authors are important for clarifying the role of immunological processes, including microbiome-dependent ones, in the etiopathogenesis of IBD. Key words: inflammatory bowel disease, ulcerative colitis, Crohn’s disease, T-helper cell subsets, cytokines, chemokines, gut microbiome

What Do Influenza and COVID-19 Represent for Patients With Inflammatory Bowel Disease?

BackgroundInflammatory bowel diseases (IBD) are a group of immune and inflammatory diseases; and patients seem to be more vulnerable to influenza and coronavirus disease 2019 (COVID-19). These conditions are characterized by the augmented release of inflammatory cytokines that have been suggested as potential triggers for the acute respiratory distress syndrome, which may favor severe and even fatal outcomes. For these reasons, this review aims to evaluate what influenza and COVID-19 may represent for patients with IBD.MethodsThe search was performed in MEDLINE/PubMed, EMBASE, and Cochrane databases. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to build the review.ResultsThe conventional therapies used by IBD patients may also interfere in the outcomes of influenza and COVID-19. Immune-suppressors agents are associated with a higher risk of infections due to the inhibition of intracellular signals necessary to the host act against pathogens. On the other hand, drugs related to the suppression of the production of cytokines in IBD could bring benefits to reduce mucosal inflammation, and for preventing pneumonia. Moreover, coronaviruses can bind to the target cells through angiotensin-converting enzyme 2 (ACE-2) receptor that is expressed in epithelial cells of the lung and largely the colon and the terminal ileum suggesting that human intestinal tract could be an alternative route for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).ConclusionsOnce the cytokine storm observed in influenza and COVID-19 is similar to the cytokine pattern observed in IBD patients during the disease flares, the advice is that avoiding the infections is still an optimal option for IBD subjects.

NOX1-derived ROS drive the expression of Lipocalin-2 in colonic epithelial cells in inflammatory conditions.

Inflammatory bowel disease (IBD) is characterized by severe and recurrent inflammation of the gastrointestinal tract, associated with altered patterns of cytokine synthesis, excessive reactive oxygen species (ROS) production, and high levels of the innate immune protein, lipocalin-2 (LCN-2), in the mucosa. The major source of ROS in intestinal epithelial cells is the NADPH oxidase NOX1, which consists of the transmembrane proteins, NOX1 and p22PHOX, and the cytosolic proteins, NOXO1, NOXA1, and Rac1. Here, we investigated whether NOX1 activation and ROS production induced by key inflammatory cytokines in IBD causally affects LCN-2 production in colonic epithelial cells. We found that the combination of TNFα and IL-17 induced a dramatic upregulation of NOXO1 expression that was dependent on the activation of p38MAPK and JNK1/2, and resulted into an increase of NOX1 activity and ROS production. NOX1-derived ROS drive the expression of LCN-2 by controlling the expression of IκBζ, a master inducer of LCN-2. Furthermore, LCN-2 production and colon damage were decreased in NOX1-deficient mice during TNBS-induced colitis. Finally, analyses of biopsies from patients with Crohn's disease showed increased JNK1/2 activation, and NOXO1 and LCN-2 expression. Therefore, NOX1 might play a key role in mucosal immunity and inflammation by controlling LCN-2 expression.

Effects of Anti-Integrin Treatment With Vedolizumab on Immune Pathways and Cytokines in Inflammatory Bowel Diseases.

Despite proven clinical efficacy of vedolizumab (VDZ) for inducing and maintaining remission in patients with Crohn's disease (CD) and ulcerative colitis (UC), subgroups of patients have no therapeutic benefit from anti-α4β7 integrin therapy with VDZ. Within this study, we aimed to identify genetic, cellular, and immunological mechanisms that define response and failure to VDZ treatment. Intestinal RNA sequencing was performed in UC and CD patients before and at week 14 of VDZ therapy. α4β7 expression on peripheral and mucosal immune cells was assessed by flow cytometry and immunohistochemistry. Cellular modes of VDZ-mediated action were analyzed ex vivo and in VDZ-treated inflammatory bowel disease patients. Transcriptome analysis showed an impairment of signaling cascades associated with adhesion, diapedesis, and migration of granulocytes and agranulocytes upon VDZ therapy. In non-remitters to VDZ therapy, a tissue destructive and leukocyte-mediated inflammatory activity with activation of TNF-dependent pathways was present, all of which were inhibited in remitters to VDZ. Clinical remission was associated with a significant reduction of α4β7 expression on Th2 and Th17 polarized mucosal CD4+ T cells at week 14 of VDZ therapy and with significantly higher numbers of α4β7-expressing mucosal cells prior to the initiation of VDZ therapy compared with non-remitters. Intestinal α4β7 expression prior to VDZ therapy might represent a biomarker that predicts therapeutic response to subsequent VDZ treatment. Due to high activation of TNF signaling in VDZ non-remitters, anti-TNF treatment might represent a promising therapeutic strategy in VDZ refractory patients.

РОЛЬ НАРУШЕНИЙ РЕОЛОГИЧЕСКИХ СВОЙСТВ ЭРИТРОЦИТОВ В ПАТОГЕНЕЗЕ ВОСПАЛИТЕЛЬНЫХ ЗАБОЛЕВАНИЙ КИШЕЧНИКА У ДЕТЕЙ

Цель исследования: изучение роли нарушений реологических свойств эритроцитов в патогенезе воспалительных заболеваний кишечника у детей. Материалы и методы. Обследовано 37 детей с воспалительными заболеваниями кишечника (ВЗК): 17 детей с болезнью Крона (БК) и 20 — с язвенным колитом (ЯК). Исследовали деформируемость эритроцитов, спонтанную агрегацию тромбоцитов в искусственном сдвиговом потоке, динамическую вязкость крови, морфологию агрегатов эритроцитов, состояние цитоскелета эритроцитов методом термоиндукции, состояние гемостаза на тромбоэластографе, среднемолекулярные пептиды, сорбционную емкость эритроцитов, связывающую способность альбумина. Результаты. Выявлено, что ВЗК сопровождаются значительным ухудшением гемореологических свойств крови, что является важным фактором патогенеза этих заболеваний и лежит в основе нарушений микроциркуляции при ВЗК. Установлено, что при БК нарушения большинства исследованных показателей не только существеннее, чем при ЯК, но и стабильнее — они сохраняются даже после проведенного лечения. Также как и реологические нарушения, эндогенная интоксикация сохраняется при БК и после проведенного лечения. Заключение. Нарушения реологических свойств крови являются важным фактором, обуславливающим ишемические повреждения кишечника. Это дает основание рекомендовать использование при ВЗК адъювантных методов борьбы с гипоксией и нарушениями микроциркуляции. Aim: to study the role of disturbances in erythrocytes rheological properties in pathogenesis of inflammatory bowel diseases (IBD) in children. Materials and methods. The study included 37 patients with IBD: 17 with Crohn’s disease (CD) and 20 with ulcerative colitis (UC). Erythrocyte deformability, spontaneous platelet aggregation, dynamical blood viscosity, morphology of erythrocyte aggregates, the state of erythrocyte cytoskeleton by thermoinduction method, hemostasis state by thromboelastograph, medium molecular peptides, erythrocyte sorption capacity, binding ability of albumin were researched. Results. We revealed that IBD accompanied by a significant degradation of blood hemorheological properties. It is an important factor in the pathogenesis of these diseases and is at the core of microcirculation disorders at IBD. It was found that at CD disorders the majority of studied parameters were not only more significant than in UC, but they also remained much more stable even after the treatment. At CD endogenous intoxication as well as rheological disorders persisted after treatment. Conclusion. Disorders of blood rheological properties are an important factor causing ischemic damage of the intestine. This gives reason for recommending the use of adjuvant methods to reduce hypoxia and microcirculatory disturbances at IBD.

Interplay of Immunity and Vitamin D: Interactions and Implications with Current IBD Therapy

Crohn's disease (CD) and ulcerative colitis (UC) are classified under inflammatory bowel disease (IBD) which has been linked to a multifaceted etiology involving both environmental and genetic factors that intersect with the vitamin D pathway. Dysfunctions in innate immune defense mechanisms in the epithelial compartment of the intestine play a crucial role in the pathogenesis of IBD. Symptoms of IBD are caused by excessive immune responses to luminal bacteria, and vitamin D has been shown to play a role in intestinal defense by aiding in the suppression of microbial invasion into the epithelium. Vitamin D, as an immunomodulator, can modify the innate immune response of the body. Vitamin D attenuates the transcription of pro-inflammatory cytokines that are upregulated in the event of epithelial stress common in patients with IBD. Vitamin D deficiency was identified in 82% of IBD patients compared to the 31% national average and has been linked to defective epithelial processes at both genomic and proteomic levels. Mucosal damage and an impaired immune response are at the center of IBD, and vitamin D aids in sustaining the structural integrity of epithelial cells while enhancing innate immune responses in the mucosa. Here we provide a systematic review of the pathophysiological effects of cytokines in IBD in the presence of vitamin D deficiency. Also, analysis of the immunomodulatory effect of vitamin D in regulating immunopathogenic factors like chemokines, growth factors, and human defensins will enhance knowledge of the underlying molecular mechanisms of the therapeutic role of vitamin D in IBD and thus aid in the development of better patient management strategies.

MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis.

Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP) each, LL-37/hCAP-18 and Cramp, respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity against Entamoeba histolytica are not well characterized. In this study, we quantified whether MUC2 expression and release could regulate the expression and secretion of cathelicidin LL-37 in colonic epithelial cells and in the colon. The synthesis of LL-37 was enhanced with butyrate (a product of bacterial fermentation) and interleukin-1β (IL-1β) (a proinflammatory cytokine in colitis) in the presence of exogenously added purified MUC2. The LL-37 responses to butyrate and IL-1β were higher in high-MUC2-producing cells than in lentivirus short hairpin RNA (shRNA) MUC2-silenced cells. Activation of cyclic adenylyl cyclase (AMP) and mitogen-activated protein kinase (MAPK) signaling pathways was necessary for the simultaneous expression of MUC2 and cathelicidins. In Muc2 mucin-deficient (Muc2-/-) mice, murine cathelicidin (Cramp) was significantly reduced compared to that in Muc2+/- and Muc2+/+ littermates. E. histolytica-induced acute inflammation in colonic loops stimulated high levels of cathelicidin in Muc2+/+ but not in Muc2-/- littermates. In dextran sodium sulfate (DSS)-induced colitis in Muc2+/+ mice, which depletes the mucus barrier and goblet cell mucin, Cramp expression was significantly enhanced during restitution. These studies demonstrate regulatory mechanisms between MUC2 and cathelicidins in the colonic mucosa where an intact mucus barrier is essential for expression and secretion of cathelicidins in response to E. histolytica- and DSS-induced colitis.