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Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn's disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn's disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn's disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn's disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner.

Fat tissue was initially described for its endocrine and metabolic function. Over the last two decades increasing evidence indicated a close interaction with the immune system. Partly responsible for this immune modulatory function are soluble factors released by the fat tissue, most prominently the so-called adipokines. These discoveries led to the question how adipokines influence inflammatory diseases. Linking inflammation and adipose tissue, Crohn's disease, a chronic inflammatory bowel disease, is of particular interest for studying the immune modulatory properties of adipokines since it is characterized by a hyperplasia of the mesenteric fat that subsequently is creeping around the inflamed segments of the small intestine. Thus, the role of several adipokines in the creeping fat as well as in intestinal inflammation was recently explored. The present review selected the four adipokines adiponectin, apelin, chemerin, and leptin and provides a working model based on the available literature how these factors participate in the maintenance of intestinal immune homeostasis.

Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.

Purpose of Review: The composition of activated adipose tissue with adipocytes secreting a broad spectrum of immune-modulatory adipokines next to adipose tissue-derived stromal cells and professional immune effector cells in the visceral fat creates a complex network of inflammatory processes shaping local immune responses in the adjacent inflamed intestinal mucosa., Recent Findings: In Crohn's disease a particular phenomenon called 'creeping fat' can be observed. Here the hyperplastic mesenteric fat tissue not only grows around inflamed small intestinal segments but also furthermore affects the regulation of the mucosal immune system. Diverticular disease is highly prevalent in the western world but the knowledge about its immunopathology remains incomplete. Interestingly, adipose tissue also frequently covers the basolateral site of inflamed diverticula, hence locally reflecting the phenomenon seen in Crohn's disease., Summary: This review aims to summarize the current knowledge in which measures this intraabdominal fat participates in the regulation of intestinal inflammation with a particular focus on differences and possible parallels in Crohn's disease and diverticulitis. The available data allow for suggesting that each inflamed diverticula mechanistically reflects Crohn's disease on a miniature scale.

Modifying the chromatin structure and interacting with non-histone proteins, histone deacetylases (HDAC) are involved in vital cellular processes at different levels. We here specifically investigated the direct effects of HDAC5 in macrophage activation in response to bacterial or cytokine stimuli. Using murine and human macrophage cell lines, we studied the expression profile and the immunological function of HDAC5 at transcription and protein level in over-expression as well as RNA interference experiments. Toll-like receptor-mediated stimulation of murine RAW264.7 cells significantly reduced HDAC5 mRNA within 7 hrs but presented baseline levels after 24 hrs, a mechanism that was also found for Interferon-γ treatment. If treated with lipopolysaccharide, RAW264.7 cells transfected for over-expression only of full-length but not of mutant HDAC5, significantly elevated secretion of tumour necrosis factor α and of the monocyte chemotactic protein-1. These effects were accompanied by increased nuclear factor-κB activity. Accordingly, knock down of HDAC5-mRNA expression using specific siRNA significantly reduced the production of these cytokines in RAW264.7 or human U937 cells. Taken together, our results suggest a strong regulatory function of HDAC5 in the pro-inflammatory response of macrophages., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Purpose of Review: This review summarizes current knowledge on the contribution of mesenteric adipose tissue in intestinal inflammation. We will describe the cellular and humoral characteristics of creeping fat, their potential impact for Crohn's disease and propose a working model for the critical interplay between the creeping fat and the inflamed intestine., Recent Findings: Creeping fat can be distinguished from healthy adipose tissue by its distinctively small adipocytes, by a specific microenvironment defined by high levels of adipokines and by a dominant immune cell infiltration. In Crohn's disease transmural inflammation facilitates increased bacterial translocation into the creeping fat. Translocalizing antigens can directly activate (pre)adipocytes via innate receptors. Adipocyte-derived mediators modulate phenotype and function of innate and adaptive immune cells. Activated (pre)adipocytes and adipokine-modulated immune cells might support a degree of inflammatory activation within the creeping fat that allows competent immune defense against exogenous factors while preventing systemic inflammation., Summary: Fat tissue as an active organ in health and disease has been ignored for too long. The last few years of research provided evidence for the complex metabolic and immunological functions of adipose tissue. On the basis of the available data, creeping fat in Crohn's disease exerts a protective function by a localized anti-inflammatory effect, thus preventing a systemic inflammatory response.

Histone deacetylase inhibitors are potent inducers of growth arrest and apoptotic cell death and are currently in clinical studies for solid tumors. In addition, recent studies from our own group provide evidence for an anti-inflammatory potency of HDACi in vitro and in vivo by using various models of experimental colitis. Since inflammatory bowel disease in humans is associated with an increased risk of developing colorectal cancer, a therapeutic approach combining anti-inflammatory as well as antiprolif-erative properties is highly intriguing. Consequently, methods to further characterize the mechanisms involved include the direct analysis of the acetylation/deacetylation as well as the regulatory effect of histone deacetylase inhibitors on defined cell populations.

Background: Gut bacteria trigger colitis in animal models and are suspected to aggravate inflammatory bowel diseases. We have recently reported that Escherichia coli accumulates in murine ileitis and exacerbates small intestinal inflammation via Toll-like receptor (TLR) signaling., Methodology and Principal Findings: Because knowledge on shifts in the intestinal microflora during colitis is limited, we performed a global survey of the colon flora of C57BL/10 wild-type (wt), TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice treated for seven days with 3.5% dextrane-sulfate-sodium (DSS). As compared to wt animals, TLR2(-/-), TLR4(-/-), and TLR2/4(-/-) mice displayed reduced macroscopic signs of acute colitis and the amelioration of inflammation was associated with reduced IFN-gamma levels in mesenteric lymph nodes, lower amounts of neutrophils, and less FOXP3-positive T-cells in the colon in situ. During acute colitis E. coli increased in wt and TLR-deficient mice (P<0.05), but the final numbers reached were significantly lower in TLR2(-/-), TLR4(-/-) and TLR2/4(-/-) animals, as compared to wt controls (P<0.01). Concentrations of Bacteroides/ Prevotella spp., and enterococci did not increase during colitis, but their numbers were significantly reduced in the colon of DSS-treated TLR2/4(-/-) animals (P<0.01). Numbers of lactobacilli and clostridia remained unaffected by colitis, irrespective of the TLR-genotype of mice. Culture-independent molecular analyses confirmed the microflora shifts towards enterobacteria during colitis and showed that the gut flora composition was similar in both, healthy wt and TLR-deficient animals., Conclusions and Significance: DSS-induced colitis is characterized by a shift in the intestinal microflora towards pro-inflammatory Gram-negative bacteria. Bacterial products exacerbate acute inflammation via TLR2- and TLR4-signaling and direct the recruitment of neutrophils and regulatory T-cells to intestinal sites. E. coli may serve as a biomarker for colitis severity and DSS-induced barrier damage seems to be a valuable model to further identify bacterial factors involved in maintaining intestinal homeostasis and to test therapeutic interventions based upon anti-TLR strategies.

Data in this study indicate that both adipocytes and preadipocytes express abroad set of TLRs and they also respond to specific stimulation by cytokine production. The may be of relevance to Crohn's disease and a suggests a closer link between adipose tissue and innate immunity.

The effect of modifying early neutrophil-mediated inflammation on the development of airway hyperresponsiveness (AHR) was investigated using an interleukin (IL)-1 receptor antagonist (IL-1Ra), an anti-IL-18 antibody (anti-IL-18) or a p38 mitogen-activated protein kinase (MAPK) inhibitor (M39). Balb/c mice were sensitized to ovalbumin (OVA) and challenged with a single intranasal dose of OVA. Treatment with the IL-1Ra or anti-IL-18 was initiated 20 min before challenge, whereas M39 was administered 4 h before the challenge. Eight hours after challenge, sensitized mice showed significantly higher numbers of neutrophils in bronchoalveolar lavage (BAL) fluid; treatment with IL-1Ra, anti-IL-18, or M39 significantly decreased the influx of neutrophils. At 48 h, none of the treatments affected eosinophil inflammation in BAL fluid and lung tissue, goblet cell hyperplasia, or cytokine levels (IL-4, IL-5, IL-12, IL-13, interferon-gamma) in BAL fluid. Anti-IL-18 or IL-1Ra had no effect on the development of AHR, whereas M39-treated mice showed a decrease in methacholine responsiveness. These results demonstrate that early neutrophil influx following allergen challenge is mediated by IL-1, IL-18, and p38 MAPK. However, neutralization of IL-1 and IL-18 did not affect the later development of AHR and eosinophilic airway inflammation. The effects of inhibiting p38 MAPK in decreasing AHR indicate activities independent of its prevention of neutrophil accumulation.

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4+CD45Rbhigh transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient ( ob/ob) CD4+ T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFα, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4+CD45Rbhigh cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNγ release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-1 is a key mediator in the pathogenesis of inflammatory bowel disease (IBD). Naturally occurring IL-1 modulators include IL-1 receptor antagonist (IL-1Ra), IL-1 soluble receptor Type I (IL-1sRI), IL-1sRII and IL-1 receptor accessory protein (AcP). Systemic and mucosal levels of IL-1 soluble receptors remain unknown in IBD. Plasma or colonic tissues were obtained from 185 consecutive unselected patients with Crohn's disease (CD) or ulcerative colitis (UC) and from 52 control subjects. Plasma and colonic explant culture supernatants were assessed for IL-1α, IL-1β, IL-1Ra, IL-1sRI and IL-1sRII. Plasma IL-1Ra levels were higher in UC (+93%) than in healthy subjects. IL-1α and IL-1β were not detected. IL-1sRII levels were marginally lower in CD (−10%) and UC (−9%), whereas IL-1sRI levels were elevated in CD (+28%) only. Plasma IL-1sRI levels correlated positively (P < 0·01) with Crohn's disease activity index (r = 0·53), C-reactive protein (r = 0·46) andα1-acid glycoprotein (r = 0·42). In colonic explant cultures, IL-1α and IL-1Ra levels were elevated in non-lesional (+233% and+185% respectively) and lesional CD (+353% and+1069%), lesional UC (+604% and+1138%), but not in non-lesional UC. IL-1β was elevated in lesional UC (+152%) and CD (+128%). In contrast, IL-1sRII levels were elevated in non-lesional CD (+65%), but remained unchanged in lesional CD, non-lesional and lesional UC. IL-1sRI levels did not differ between patient and control groups. These results indicate that (i) the proinflammatory moiety IL-1sRI is a systemic marker of inflammation and activity in CD and (ii) local shedding of the functional antagonist IL-1sRII may dampen colonic inflammation in CD, but not in UC. [ABSTRACT FROM AUTHOR]

Background: Leptin regulates appetite through the long isoform of its receptor in the hypothalamus. Although leptin regulates immune responses, it is still unknown whether a direct effect of leptin on lymphocytes is required. Aims: To clarify whether expression of leptin receptors on I lymphocytes modulates intestinal inflammation in mice. Methods: The model of colitis induced by transfer of CD4+CD45RBhigh (RBhigh) cells into scid mice was used. Wild-type (WT) or leptin receptor deficient (db/db) RBhigh cells were transferred into scid mice and development of colitis evaluated. Results: Leptin receptors were expressed on both RBhigh and RBhigh cells. Intestinal lymphocytes of mice with colitis expressed high leptin levels compared with healthy controls whereas the opposite was true for serum leptin levels. Transfer of RBhigh cells from db/db mice induced delayed disease compared with transfer of WT cells. A high rate of apoptosis in lamina propria lymphocytes and reduced cytokine production were observed early on in scid mice receiving db/db RBhigh cells. These effects were not due to the high levels of glucocorticoids present in db/db mice as administration of corticosterone to WT mice failed to reproduce this phenomenon. High expression of peroxisome proliferator activated receptor γ was observed in the colon of recipients of db/db compared with WT cells. Freshly isolated db/db RBhigh cells produced low levels of interferon γ. Despite delayed onset of colitis, as disease progressed differences between mice receiving WT or db/db cells were no longer apparent. Conclusions: These results suggest that leptin affects the immune response, partly by acting on the long isoform of its receptor expressed on T lymphocytes. [ABSTRACT FROM AUTHOR]

SUMMARY Interleukin-18 (IL-18), derived from macrophages and Kupffer cells, is the central pro-inflammatory cytokine leading to experimental liver failure. IL-18 binding protein (IL-18BP) is a circulating protein that binds IL-18 and neutralizes its activity. Since IL-18 production is increased in chronic HCV infection, we asked whether IFN-α might act on the IL-18/IL-18BP system in HCV patients. IL-18BP, total and free IL-18 plasma levels were determined in 13 HCV patients receiving 1 × 107 IU IFN-α subcutaneously daily for 28 days. The in vitro effects of IFN-α on macrophage IL-18BP and IL-18 were studied by enzyme-linked immunosorbent assays and Northern analysis. IFN-α administration increased IL-18BP plasma levels 3·24 fold 24 h after institution of therapy, resulting in a 67·4% reduction of free IL-18. Total IL-18 levels decreased from day +24 on. In vitro , IFN-α diminished IL-18 release from macrophages of healthy volunteers and chronic HCV patients. On top of its inhibitory effects on IL-1 and TNF-α release, IFN-α also exerts its anti-inflammatory action in vivo by induction of IL-18BP. These anti-inflammatory properties might account – together with its antiviral action – for its clinical efficacy in chronic hepatitis C. [ABSTRACT FROM AUTHOR]