Perpetuation Of Chronic Inflammation Research Articles

Clinical trial of a probiotic and herbal supplement for lung health.

Dysbiosis of the gut microbiome may augment lung disease via the gut-lung axis. Proteobacteria may contribute to tissue proteolysis followed by neutrophil recruitment, lung tissue injury, and perpetuation of chronic inflammation. To study the effects of probiotics across the gut-lung axis, we sought to determine if a Lactobacillus probiotic and herbal blend was safe and well-tolerated in healthy volunteers and asthmatic patients. We conducted a 1-month randomized, open-label clinical trial in Cork, Ireland with healthy and asthmatic patients who took the blend twice a day. The primary endpoint was safety with exploratory endpoints including quality of life, lung function, gut microbiome ecology, and inflammatory biomarkers. All subjects tolerated the blend without adverse events. Asthmatic subjects who took the blend showed significant improvements in lung function as measured by forced expiratory volume and serum short chain fatty acid levels from baseline to Week 4. The gut microbiome of asthmatic subjects differed significantly from controls, with the most prominent difference in the relative abundance of the proteobacteria Escherichia coli. Administration of the probiotic maintained overall microbial community architecture with the only significant difference being an increase in absolute abundance of the probiotic strains measured by strain-specific PCR. This study supports the safety and efficacy potential of a Lactobacillus probiotic plus herbal blend to act on the gut-lung axis. However, due to the lack of a control group, a longer blinded, placebo-controlled study will be warranted to confirm the efficacy improvements observed in this trial. https://clinicaltrials.gov/, identifier NCT05173168.

Highlights of Strategies Targeting Fibroblasts for Novel Therapies for Rheumatoid Arthritis.

Synovial fibroblasts of rheumatoid arthritis (RA) play a critical role in perpetuation of chronic inflammation by interaction with immune and inflammatory cells and in cartilage and bone invasion, but current therapies for RA are not directly targeted fibroblasts. Selectively fibroblast targeted therapy has been hampered because of lack of fibroblast specific molecular signature. Recent advancement in technology enabled us to gain insightful information concerning RA synovial fibroblast subpopulations and functions. Exploring fibroblast targeted therapies have been focused on inducing cell death via fibroblast associated proteins; interrupting fibroblast binding to matrix protein; blocking intercellular signaling between fibroblasts and endothelial cells; inhibiting fibroblast proliferation and invasion; promoting cell apoptosis and inducing cellular senescence, and modulating fibroblast glucose metabolism. Translation into clinical studies of these fibroblast targeted strategies is required for evaluation for their clinical application, in particular for combination therapy with current immune component targeted therapies. Here, several strategies of fibroblast targeted therapy are highlighted.

Pathogenetic and clinical aspects of interleukin 17 blockade in spondylitis

This article presents analysis of current data highlighted the problem of pathogenic mechanism of the most common spondyloarthritides (SpA) and focused on the pivotal role of interleukin‑17 in immune inflammation realization. Contribution of IL‑17 in mechanism of SpA particularly in different organ damage, in perpetuation of chronic inflammation and in structural progression is discussed. The clinical and experimental evidence of close relationship between IL‑17A levels, on one hand, and disease activity, high tempo of joint and bone affection as well as SpA extra-articular manifestations, on the other, are presented. Contribution of cell-mediated immune response including activated IL‑17A-producing cells to the pathogenesis of different SpA phenotypes is shown. Great attention is paid to the clinical effects of IL‑17A inhibition in Sp A. The results of clinical trials of novel IL‑17A inhibitor netakimab in the treatment of ankylosing spondylitis are presented. These data have demonstrated high efficacy and safety of tried preparation used in the regimen 120 mg per 2 weeks. On the basis of performed analysis the key role of IL‑17 in SpA pathogenesis is confirmed and expediency of SpA target therapy with novel IL‑17A inhibitor netakimab is justified.

Links Between Inflammatory Bowel Disease and Chronic Obstructive Pulmonary Disease

Inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the gastrointestinal and respiratory tracts, respectively. These mucosal tissues bear commonalities in embryology, structure and physiology. Inherent similarities in immune responses at the two sites, as well as overlapping environmental risk factors, help to explain the increase in prevalence of IBD amongst COPD patients. Over the past decade, a tremendous amount of research has been conducted to define the microbiological makeup of the intestine, known as the intestinal microbiota, and determine its contribution to health and disease. Intestinal microbial dysbiosis is now known to be associated with IBD where it impacts upon intestinal epithelial barrier integrity and leads to augmented immune responses and the perpetuation of chronic inflammation. While much less is known about the lung microbiota, like the intestine, it has its own distinct, diverse microflora, with dysbiosis being reported in respiratory disease settings such as COPD. Recent research has begun to delineate the interaction or crosstalk between the lung and the intestine and how this may influence, or be influenced by, the microbiota. It is now known that microbial products and metabolites can be transferred from the intestine to the lung via the bloodstream, providing a mechanism for communication. While recent studies indicate that intestinal microbiota can influence respiratory health, intestinal dysbiosis in COPD has not yet been described although it is anticipated since factors that lead to dysbiosis are similarly associated with COPD. This review will focus on the gut-lung axis in the context of IBD and COPD, highlighting the role of environmental and genetic factors and the impact of microbial dysbiosis on chronic inflammation in the intestinal tract and lung.

Differential contribution of bone marrow-derived infiltrating monocytes and resident macrophages to persistent lung inflammation in chronic air pollution exposure

Chronic exposure to particulate matter < 2.5µ (PM2.5) has been linked to cardiopulmonary disease. Tissue-resident (TR) alveolar macrophages (AΦ) are long-lived, self-renew and critical to the health impact of inhalational insults. There is an inadequate understanding of the impact of PM2.5 exposure on the nature/time course of transcriptional responses, self-renewal of AΦ, and the contribution from bone marrow (BM) to this population. Accordingly, we exposed chimeric (CD45.2/CD45.1) mice to concentrated PM2.5 or filtered air (FA) to evaluate the impact on these end-points. PM2.5 exposure for 4-weeks induced an influx of BM-derived monocytes into the lungs with no contribution to the overall TR-AΦ pool. Chronic (32-weeks) PM2.5 exposure on the other hand while associated with increased recruitment of BM-derived monocytes and their incorporation into the AΦ population, resulted in enhanced apoptosis and decreased proliferation of TR-AΦ. RNA-seq analysis of isolated TR-AΦ and BM-AΦ from 4- and 32-weeks exposed mice revealed a unique time-dependent pattern of differentially expressed genes. PM2.5 exposure resulted in altered histological changes in the lungs, a reduced alveolar fraction which corresponded to protracted lung inflammation. Our findings suggest a time-dependent entrainment of BM-derived monocytes into the AΦ population of PM2.5 exposed mice, that together with enhanced apoptosis of TR-AΦ and reorganization of transcriptional responses, could collectively contribute to the perpetuation of chronic inflammation.

The inflammatory effect of epigenetic factors and modifications in type 2 diabetes.

Inflammation has a central role in the etiology of type 2 diabetes (T2D) and its complications. Both genetic and epigenetic factors have been implicated in the development of T2D-associated inflammation. Epigenetic mechanisms regulate the function of several components of the immune system. Diabetic conditions trigger aberrant epigenetic alterations that contribute to the progression of insulin resistance and β-cell dysfunction by induction of inflammatory responses. Thus, targeting epigenetic factors and modifications, as one of the underlying causes of inflammation, could lead to the development of novel immune-based strategies for the treatment of T2D. The aim of this review is to provide an overview of the epigenetic mechanisms involved in the propagation and perpetuation of chronic inflammation in T2D. We also discuss the possible anti-inflammatory approaches that target epigenetic factors for the treatment of T2D.

Spray-drying process preserves the protective capacity of a breast milk-derived Bifidobacterium lactis strain on acute and chronic colitis in mice

Gut microbiota dysbiosis plays a central role in the development and perpetuation of chronic inflammation in inflammatory bowel disease (IBD) and therefore is key target for interventions with high quality and functional probiotics. The local production of stable probiotic formulations at limited cost is considered an advantage as it reduces transportation cost and time, thereby increasing the effective period at the consumer side. In the present study, we compared the anti-inflammatory capacities of the Bifidobacterium animalis subsp. lactis (B. lactis) INL1, a probiotic strain isolated in Argentina from human breast milk, with the commercial strain B. animalis subsp. lactis BB12. The impact of spray-drying, a low-cost alternative of bacterial dehydration, on the functionality of both bifidobacteria was also investigated. We showed for both bacteria that the spray-drying process did not impact on bacterial survival nor on their protective capacities against acute and chronic colitis in mice, opening future perspectives for the use of strain INL1 in populations with IBD.

Wakayama symposium: interface between innate and adaptive immunity in dry eye disease.

Although the mechanism of dry eye disease is not clearly understood, it is certain that inflammation and the immune response play a major role in determining the health of the ocular surface in dry eye patients. Accurate ocular surface characterization during the early stages of dry eye disease is critical for successful treatment, because there exists no single standard, objective test to diagnose the early phase of dry eye disease. The treatment target should be direct to prevent the perpetuation of chronic inflammation and immune responses. Numerous studies have categorized dry eye disease as an autoimmune-related inflammatory disease. However, relatively little is known about how innate immune mechanisms act following a local insult, why some patients are particularly vulnerable, and why local inflammation fails to resolve in these patients. Within this review, particular attention will be given to the very early events and corresponding defense mechanism in dry eye disease. The transition from innate to adaptive immunity will also be discussed.

Targeting sTNF/TNFR1 Signaling as a New Therapeutic Strategy

Deregulation of the tumor necrosis factor (TNF) plays an important role in the initiation and perpetuation of chronic inflammation and has been implicated in the development of various autoimmune diseases. Accordingly, TNF-inhibitors are successfully used for the treatment of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, total inhibition of TNF can cause severe side effects such as an increased risk of inflammation and reactivation of tuberculosis. This is likely due to the different actions of the two TNF receptors. Whereas TNFR1 predominantly promotes inflammatory signaling pathways, TNFR2 mediates immune modulatory functions and promotes tissue homeostasis and regeneration. Therefore, the specific blockage of TNFR1 signaling, either by direct inhibition with TNFR1-selective antagonists or by targeting soluble TNF, which predominantly activates TNFR1, may prevent the detrimental effects associated with total TNF-inhibitors and constitute a next-generation approach to interfere with TNF.

9: RAGE is a cell surface nucleic acid sensor

RAGE is a multi-ligand cell surface receptor of the Immunoglobulin super-family. It is composed of three extracellular immunoglobulin-like domains (V, C1 and C2), a single trans-membrane domain and a short cytoplasmic domain. RAGE is predominately expressed in the lung under normal conditions. However, during inflammation, RAGE expression increases dramatically in tissues like the vascular system, CNS and some hematopoietic cells. RAGE ligands are structurally heterogeneous and bind to RAGE through sequence nonspecific electrostatic interactions. They include advanced glycation end products, the DNA binding protein HMGB1, several proteins of the S100 family and certain types of β -sheet fibrils such as β -amyloid. Hence, RAGE is involved in many chronic inflammatory diseases such as diabetes, Alzheimer’s disease, asthma and systemic lupus erythematosus. Using EMSA and AlphaScreen, we showed that DNA and RNA bind to RAGE in a sequence nonspecific manner through electrostatic interaction of their phosphate backbone with the V and C1 domains. Human embryonic kidney (HEK) cells expressing RAGE bound more fluorescently labelled RNA and DNA than non-expressing cells as shown by microscopy and flow cytometry. In order to investigate the effect of RAGE expression on nucleic acid (NA) sensing by endosomal TLRs, we used HEK cells expressing TLR7, TLR8, TLR13 (ssRNA) or TLR9 (DNA) together with RAGE and found that RAGE increased NA induced activation of the transcription factor NF κ B. Finally, in a mouse model of acute lung inflammation, DNA inhalation induced a strong inflammatory response in WT mice, while RAGE knockout mice displayed dramatically reduced inflammation. We show that RAGE binds NAs at the cell surface, increases their uptake and thereby amplifies the activation of endosomal TLRs. This work helps to further elucidate the function of RAGE in the development and perpetuation of chronic inflammation and presents RAGE as a promising target in the development of anti-inflammatory treatments.

Possible role of Escherichia coli in propagation and perpetuation of chronic inflammation in ulcerative colitis

BackgroundThis study investigated a possible role of Escherichia coli in propagation and perpetuation of the chronic inflammation in ulcerative colitis (UC). The lesions of UC are located superficially on the rectal and/or colonic mucosa. It is suggested that the commensal bacteria of the digestive tract may play a role in the pathogenesis of UC. Several studies have demonstrated proliferation of E. coli in the gut of UC patients. An increase in the number of E. coli in the inflamed tissue is most probably related to the abundance of iron ions produced by the bacteria.MethodsColon mucosal biopsies were collected from 30 patients with acute-phase UC, both from tissues with inflammatory changes (n = 30) and unchanged tissue with no inflammatory changes (n = 30) from the same patient. Biopsies were also taken from 16 patients with irritable bowel syndrome diarrhea who comprised the control group. Quantitative and qualitative analysis of the biopsy specimens was performed using culture methods and real-time polymerase chain reaction (PCR). Genotyping of the E. coli isolates was done using pulsed-field gel electrophoresis. Multiplex PCR was used to compare the E. coli strains for the presence of genes responsible for synthesis of iron acquisition proteins: iroN, iutA, iha, ireA, chuA, and hlyA.ResultsWe demonstrated that there was a significant increase in the number of E. coli at the sites of inflammation in patients with UC compared to the control group (P = 0.031). Comparative analysis of the restriction patterns of E. coli isolated from inflammatory and unchanged tissues showed that the local inflammatory changes did not promote specific E. coli strains. There was a significant difference in the frequency of the iroN gene in E. coli isolated from patients with UC as compared to the control group.ConclusionsThe increase in the numbers of E. coli in the inflammatory tissues is related to the presence of chuA and iutA genes, which facilitate iron acquisition during chronic intestinal inflammatory processes.

P.01.2 ADALIMUMAB FOR THE TREATMENT OF POST-OPERATIVE RECURRENCE OF CROHN'S DISEASE. A SINGLE CENTRE EXPERIENCE

Background: Tumour necrosis factor alpha (TNF-a) plays an important role in malnutrition and growth retardation in paediatric inflammatory bowel disease (IBD) due to perpetuation of chronic inflammation. One of the objectives in the management of these patients should be to optimize their growth, which may be compromised due to uncontrolled disease and the effect of steroids. We aimed to study anti-TNF treatment effect on nutritional recovery in paediatric IBD, in relation to their efficacy in clinical response, both in shortand medium-term. Methods: Retrospective analysis of our paediatric IBD patients treated with anti-TNF between January 2002 and December 2010. We evaluated clinical response as defined by changes in activity scores (Paediatric Crohn’s Disease Activity Index [PCDAI] and Paediatric Ulcerative Colitis Activity Index [PUCAI]) at 2 and 8 weeks, 6 months and 1 year after its initiation. Changes in anthropometric measures (height and weight for age and body mass index [BMI]) and biochemical modifications (ESR, CRP, haemoglobin, platelets and albumin) were evaluated at 6 and 12 months. Results: 54 patients (34 boys) received anti-TNF (44 CD, 8 UC, 2 IBDU). Age at diagnosis: 11 years 5 months. Mean time from diagnosis to anti-TNF treatment: 17 months (range 0 121). Mean age at first infusion 13 years (1.1 17.3). Mean followup 35 months and mean number of infusions per patient 17. Forty-one patients received infliximab (IFX), 21 adalimumab (ADA) and 1 certolizumab pegol. Thirty-one patients (63%) had not previously received steroids. Mean basal PCDAI and PUCAI: 28.6 (2.5 62) and 39 (27 55) respectively. Clinical response was achieved in 47 cases (87%). Remission rate was 74.2% at 2 weeks, 87.7% at 8 weeks, 90% at 6 months, and 90.6% at 12 months. Seven patients experienced a relapse at some point of the follow-up. Median steroid-free time from the beginning of anti-TNF was 25.9 months (1 76). Mean BMI prior to treatment was 17, z-score 1.04 ( 4.2, +1.64). We observed improvement of anthropometry, with a mean BMI of 19.2 [z-score 0.27 ( 2.3, +1.78)] after 12 months. Biochemical parameters improvement was also observed at 6 and 12 months, with significant reduction of inflammatory markers and increase in haemoglobin and albumin levels. Conclusions: Anti-TNF treatment shows high efficacy in obtaining and maintaining clinical remission in paediatric IBD. Furthermore it has a positive impact on the nutritional status. This effect is parallel to the decrease in disease activity.

P603 Anti-TNF treatment is effective in inducing remission and restoring nutritional status in pediatric inflammatory bowel disease

Background: Tumour necrosis factor alpha (TNF-a) plays an important role in malnutrition and growth retardation in paediatric inflammatory bowel disease (IBD) due to perpetuation of chronic inflammation. One of the objectives in the management of these patients should be to optimize their growth, which may be compromised due to uncontrolled disease and the effect of steroids. We aimed to study anti-TNF treatment effect on nutritional recovery in paediatric IBD, in relation to their efficacy in clinical response, both in shortand medium-term. Methods: Retrospective analysis of our paediatric IBD patients treated with anti-TNF between January 2002 and December 2010. We evaluated clinical response as defined by changes in activity scores (Paediatric Crohn’s Disease Activity Index [PCDAI] and Paediatric Ulcerative Colitis Activity Index [PUCAI]) at 2 and 8 weeks, 6 months and 1 year after its initiation. Changes in anthropometric measures (height and weight for age and body mass index [BMI]) and biochemical modifications (ESR, CRP, haemoglobin, platelets and albumin) were evaluated at 6 and 12 months. Results: 54 patients (34 boys) received anti-TNF (44 CD, 8 UC, 2 IBDU). Age at diagnosis: 11 years 5 months. Mean time from diagnosis to anti-TNF treatment: 17 months (range 0 121). Mean age at first infusion 13 years (1.1 17.3). Mean followup 35 months and mean number of infusions per patient 17. Forty-one patients received infliximab (IFX), 21 adalimumab (ADA) and 1 certolizumab pegol. Thirty-one patients (63%) had not previously received steroids. Mean basal PCDAI and PUCAI: 28.6 (2.5 62) and 39 (27 55) respectively. Clinical response was achieved in 47 cases (87%). Remission rate was 74.2% at 2 weeks, 87.7% at 8 weeks, 90% at 6 months, and 90.6% at 12 months. Seven patients experienced a relapse at some point of the follow-up. Median steroid-free time from the beginning of anti-TNF was 25.9 months (1 76). Mean BMI prior to treatment was 17, z-score 1.04 ( 4.2, +1.64). We observed improvement of anthropometry, with a mean BMI of 19.2 [z-score 0.27 ( 2.3, +1.78)] after 12 months. Biochemical parameters improvement was also observed at 6 and 12 months, with significant reduction of inflammatory markers and increase in haemoglobin and albumin levels. Conclusions: Anti-TNF treatment shows high efficacy in obtaining and maintaining clinical remission in paediatric IBD. Furthermore it has a positive impact on the nutritional status. This effect is parallel to the decrease in disease activity.

IL-18 Upregulates the Production of Key Regulators of Osteoclastogenesis from Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Recent data have demonstrated the importance of IL-18 in the induction and perpetuation of chronic inflammation in experimental arthritis. The aim of the present study was to elucidate whether IL-18 has any indirect effects on osteoclastogenesis by regulating the production of molecules from fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Human FLS were isolated from RA synovial tissue and cultured in vitro for three to five passages. The expression of IL-18 receptor was determined by RT-PCR. The levels of soluble receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), macrophage colony-stimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in culture supernatants were determined by ELISA. Membrane-bound RANKL expression was analyzed by flow cytometry. Both α and β chains of IL-18 receptor were confirmed in cultured FLS. IL-18 upregulated membrane-bound RANKL expression and soluble RANKL production by FLS in both time- and dose-dependent manners. In addition, IL-18 enhanced production of M-CSF, GM-CSF, and OPG from cultured FLS in a dose-dependent manner. IL-18 also increased the ratio of RANKL/OPG, suggesting that the net effect of IL-18 on FLS favors for the induction of osteoclast formation and bone resorption. In conclusion, IL-18 upregulates the production of key regulators of osteoclastogenesis from FLS in RA.

Genome-Wide Expression Profiling Identifies an Impairment of Negative Feedback Signals in the Crohn’s Disease-Associated NOD2 Variant L1007fsinsC

NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide (MDP), and variants of NOD2 are associated with chronic inflammatory diseases of barrier organs (e.g., Crohn's disease, asthma, and atopic eczema). It is known that activation of NOD2 induces a variety of inflammatory and antibacterial factors. The exact transcriptomal signatures that define the cellular programs downstream of NOD2 activation and the influence of the Crohn-associated variant L1007fsinsC are yet to be defined. To describe the MDP-induced activation program, we analyzed the transcriptomal reactions of isogenic HEK293 cells expressing NOD2(wt) or NOD2(L1007fsinsC) to stimulation with MDP. Importantly, a clear loss of function could be observed in the cells carrying the Crohn-associated variant L1007fsinsC, whereas the NOD2(wt) cells showed differential regulation of growth factors, chemokines, and several antagonists of NF-κB (e.g., TNFAIP3 [A20] and IER3). This genotype-dependent regulation pattern was confirmed in primary human myelomonocytic cells. The influence of TNFAIP3 and IER3 in the context of NOD2 signaling was characterized, and we could validate the predicted role as inhibitors of NOD2-induced NF-κB activation. We show that IER3 impairs the protective effect of NOD2(wt) against bacterial cytoinvasion. These results further our understanding of NOD2 as a first-line defense molecule and emphasize the importance of simultaneous upregulation of counterregulatory anti-inflammatory factors as an integral part of the NOD2-induced cellular program. Lack of these regulatory events due to the L1007fsinsC variant may pivotally contribute to the induction and perpetuation of chronic inflammation.

Difference between phenotypes of bone marrow and peripheral blood leukocytes indicate rheumatoid arthritis bone marrow as an important site for cell activation and proliferation

Objectives Although the pathogenesis of RA is still unknown, recent data suggest bone marrow compartment is an important site contributing to the initiation and perpetuation of chronic inflammation that may spread to the joint. The aim of the present study was to compare phenotypes of bone marrow and peripheral blood leukocytes isolated from rheumatoid arthritis (RA) and osteoarthritis (OA) patients that may indicate whether bone marrow is implicated in the activation and propagation of mature leukocytes. Methods Mononuclear cells were isolated from peripheral blood and bone marrow of patients with RA and OA undergoing hip replacement. Sodium citrate was used as an anticoagulant. To assess cell phenotypes, specific monoclonal antibodies against: CD3, CD19, CD20, CD4, CD8, CD16, CD56, CD38, CD27, CD25, CD69, CD14, CD123, CD11c, HLA-DR, BDCA-1 and BDCA-2 were used for staining, followed by flow cytometric analysis. Results Preliminary results indicate that RA bone marrow compartment contained different proportions of activated CD4+ and CD8+ T cell, B-cells, NK-cells and macrophages than paired peripheral blood. Unlike in peripheral blood from RA and OA, where relatively small differences in cell phenotypes were detected, composition of bone marrow mononuclear cells differed substantially between these two diseases. Conclusions Phenotypic differences between leukocytes from bone marrow and peripheral blood indicate that in RA bone marrow microenvironment provides stronger signals leading to activation and maturation of leukocytes than in OA. Thus, these data support notion that bone marrow actively participates in the pathogenesis of RA. Acknowledgements This work was partially supported by funds from the European Community's FP6 Project 018661 Autocure.

Interleukin-18 as a potential target in inflammatory arthritis.

To date, the mechanisms underlying the aetiology of rheumatoid arthritis (RA) remain poorly understood. However, targeting tumour necrosis factor (TNF)-α in the clinic represents an exciting and important advance, in both therapeutics and understanding of disease pathogenesis. Non-responder or partial responder patients are not uncommon and disease usually flares on discontinuation of treatment [1]. Thus novel, pathogenesis-led interventions are required. Our group has studied cytokine networks in RA synovial membrane, identifying pathways regulating T lymphocyte function and TNF-α production that result in inflammatory synovitis. Interleukin (IL)-18, a member of the interleukin-1 cytokine superfamily, recognized as an important regulator of both innate and acquired immunity, is one such cytokine. We identified IL-18 expression within the inflamed synovium of RA patients [2] and similar reports document its presence in other autoimmune and chronic inflammatory diseases, in cancers and in numerous infectious diseases. This editorial will review function and focus on recent data including an article in this issue of Clinical and Experimental Immunology in which Ye and colleagues [3] provide data supporting a role for IL-18 in the induction and perpetuation of chronic inflammation during experimental and clinical RA. Activities in additional disease states and during infection have been discussed recently elsewhere [4–6].

Stimulation of peripheral blood and intestinal mucosa cells by synthetic CpG oligodeoxynucleotides

The breakdown of tolerance to autologous bacterial flora has been implicated as a major factor contributing to the initiation and perpetuation of chronic inflammation in inflammatory bowel diseases (IBD). To test whether bacterial DNA is at the origin of inflammation in IBD, we have examined the response of lamina propria (LPMC) or peripheral mononuclear cells (PBMC) and purified T cells from IBD patients and control patients to stimulations with a set of oligodeoxynucleotides (ODNs) characterized by the presence or absence of cytosine-guanosine dinucleotides (CpG) and/or 3′ poly-guanosine (poly-G) extension. Furthermore we have evaluated the costimulatory activities of these ODNs on T cells activated via CD2 or CD3 pathway. We demonstrated that CpG ODNs induce higher proliferation of LPMC from inflammatory intestinal mucosa compared to healthy mucosa. We confirmed that CpG ODNs do not directly costimulate peripheral blood T cells activated by CD3 pathway. Finally, we revealed that CpG or non-CpG ODNs with 3′ poly-G extension inhibit completely CD2 activation of purified PB or LP T-cells whereas only CpG ODNs without poly-G extension enhance proliferation and IFN-γ production of PB T cells stimulated by CD2 pathway only in presence of NK and NK T cells. Our data suggest that NK T cells may be the primary target of ODNs and play a crucial role in indirect T-cell activation by ODN.

Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice.

The cytokines TNF and IL-1 have been implicated as mediators of the inflammatory processes in patients with inflammatory bowel disease (IBD). To investigate the role of these cytokines in mucosal inflammation we used anti-cytokine strategies in a mouse model of acute and chronic colitis. Mice which received 5% dextran sulphate sodium (DSS) in their drinking water showed signs of acute colitis on day 4, with severe weight loss and bloody diarrhoea. Chronic colitis was established after four cycles of feeding 5% DSS for 7 days and water for 10 days, with the mice showing diarrhoea but no weight loss. In acute colitis, treatment with anti-IL-1 reagents, anti-TNF MoAb, or dexamethasone (DEX) led to aggravation. By contrast, in chronic colitis, treatment of mice with several IL-1 activity-inhibiting reagents failed to show significant effects, whereas anti-TNF MoAb or DEX significantly reduced the colitis. We conclude that in acute colitis IL-1 and TNF are beneficial, whereas in chronic colitis, TNF but not IL-1 seems to play a major role in perpetuation of chronic inflammation.

Role of interleukin 18 in rheumatoid arthritis

Mediators produced by innate immune response cells such as macrophages can profoundly influence adaptive immunity. Recent studies have shown that interleukin (IL) 18 has an influential role in inflammatory response....