[Show abstract][Hide abstract] ABSTRACT: Psoriasis is a common chronic inflammatory disease with characteristic skin alterations functioning as a model of immune-mediated disorders. Cytokines play a key role in psoriasis pathogenesis. Here, we demonstrated that out of 30 individually quantified cytokines IL-19 showed the strongest differential expression between psoriatic lesions and healthy skin. Cutaneous IL-19 overproduction was reflected by elevated IL-19 blood levels that correlated with psoriasis severity. Accordingly, anti-psoriatic therapies substantially reduced both cutaneous and systemic IL-19 levels. IL-19 production was induced in keratinocytes by IL-17 A and further amplified by TNF-α and IL-22. Among skin cells, keratinocytes were found to be important targets of IL-19. IL-19 alone however regulated only a few keratinocyte functions. While increasing the production of S100A7/8/9 and, to a moderate extent, also IL-1β, IL-20, CXCL8, and MMP1, IL-19 had no clear influence on the differentiation, proliferation or migration of these cells. Importantly, IL-19 amplified many IL-17 A effects on keratinocytes, including the induction of β-defensins, IL-19, IL-23p19, and Th17-cell- and neutrophil-attracting chemokines. In summary, IL-19 as a component of the IL-23/IL-17 axis strengthens the IL-17 A action and might be a biomarker for the activity of this axis in chronic inflammatory disorders.Journal of Investigative Dermatology accepted article preview online, 21 July 2014; doi:10.1038/jid.2014.308.
The Journal of investigative dermatology. 07/2014;
[Show abstract][Hide abstract] ABSTRACT: To evaluate intensity, localization and cofactors of pain in Crohn's disease and ulcerative colitis patients in connection with health-related quality of life (HRQOL) and disease activity.
We reviewed and analyzed the responses of 334 patients to a specifically designed questionnaire based on the short inflammatory bowel disease questionnaire (SIBDQ) and the German pain questionnaire. Pain intensity, HRQOL, Crohn's disease activity index (CDAI) and colitis activity index (CAI) were correlated and verified on a visual analog scale (VAS).
87.9% of patients reported pain. Females and males reported comparable pain intensities and HRQOL. Surgery reduced pain in both genders (P = 0.023), whereas HRQOL only improved in females. Interestingly, patients on analgesics reported more pain (P = 0.003) and lower HRQOL (P = 0.039) than patients not on analgesics. A significant correlation was found in UC patients between pain intensity and HRQOL (P = 0.023) and CAI (P = 0.027), and in CD patients between HRQOL and CDAI (P = 0.0001), but not between pain intensity and CDAI (P = 0.35). No correlation was found between patients with low CDAI scores and pain intensity.
Most IBD patients suffer from pain and have decreased HRQOL. Our study reinforces the need for effective individualized pain therapy in IBD patients.
World Journal of Gastroenterology 07/2010; 16(25):3168-77. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Osteopontin (OPN) is characterized as a major amplifier of Th1-immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild-type (WT) mice with dextran sodium sulfate (DSS)-induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN-deficient (OPN(-/-)) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN(-/-) mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)-1 beta and matrix metalloproteinases was found in acute colitis of OPN(-/-) mice. This was associated with decreased blood levels of IL-22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN-(/-) mice showed increased serum levels of tumour necrosis factor (TNF)-alpha, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS-colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN(-/-) mice were protected from mucosal inflammation and demonstrated lower serum levels of IL-12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn's disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation.
Journal of Cellular and Molecular Medicine 06/2009; 13(6):1162-74. · 4.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The coincidence between infections with parasitic worms and the reduced prevalence of allergic disease in humans and in animal models has prompted the search for helminth molecules with antiallergic and antiinflammatory potential. We report herein that filarial cystatin, a secreted protease inhibitor of filarial nematodes, suppresses Th2-related inflammation and the ensuing asthmatic disease in a murine model of OVA-induced allergic airway responsiveness. Treatment with recombinant filarial cystatin inhibited eosinophil recruitment, reduced levels of OVA-specific and total IgE, down-regulated IL-4 production, and suppressed allergic airway hyperreactivity when applied during or after sensitization and before challenge with the allergen. Depletion of macrophages by clodronate-containing liposomes prevented the curative effects and restored the levels of infiltrating cells, IgE, and allergic airway reactivity. Blocking of IL-10 by application of anti-IL-10 receptor Abs restored the reduced number of infiltrating cells and the levels of OVA-specific IgE. In contrast, depletion of regulatory T cells by anti-CD25 Abs had only limited effects. Cystatin also modulated macrophage-mediated inflammation in a murine model of dextran sulfate sodium-induced colitis, leading to reduction of inflammatory infiltrations and epithelial damage. Our data demonstrate that treatment with a single helminth protein can exert the antiallergic effects of helminth infections.
The Journal of Immunology 04/2008; 180(6):4265-72. · 5.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Galectins have recently emerged as central regulators of the immune system. We have previously demonstrated that carbohydrate-dependent binding of galectin-2 induces apoptosis in activated T cells. Here, we investigate the potential therapeutic effect of galectin-2 in experimental colitis. Galectin-2 expression and its binding profile were determined by immunohistochemistry. Acute and chronic colitis was induced by dextran sodium sulfate administration and in a T-cell transfer colitis model. Apoptosis was assessed by TdT-mediated dUTP-biotin nick-end labeling, and cytokine secretion was determined by cytometric bead array. We show that galectin-2 was constitutively expressed mainly in the epithelial compartment of the mouse intestine and bind to lamina propria mononuclear cells. During colitis, galectin-2 expression was reduced, but could be restored to normal levels by immunosuppressive treatment. Galectin-2 treatment induced apoptosis of mucosal T cells and thus ameliorated acute and chronic dextran-sodium-sulfate-induced colitis and in a T-helper-cell 1-driven model of antigen-specific transfer colitis. Furthermore, the pro-inflammatory cytokine release was inhibited by galectin-2 treatment. In preliminary toxicity studies, galectin-2 was well tolerated. Our study provides evidence that galectin-2 induces apoptosis in vivo and ameliorates acute and chronic murine colitis. Furthermore, galectin-2 has no significant toxicity over a broad dose range, suggesting that it may serve as a new therapeutic agent in the treatment of inflammatory bowel disease.
Journal of Molecular Medicine 01/2008; 86(12):1395-406. · 4.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Centocor Inc is developing CNTO-1275 (ustekinumab), a subcantaneous mAb against the p40 subunit of IL-12 and IL-23, for the potential treatment of inflammatory diseases such as psoriasis, psoriatic arthritis, multiple sclerosis (MS) and Crohn's disease (CD). In July 2004, a phase II trial for MS had commenced, and by July 2006 this study was no longer recruiting patients. By May 2005, CNTO-1275 was in phase II studies for CD, and by January 2006 the antibody was in phase III studies for psoriasis. In December 2005, a phase II trial in patients with psoriatic arthritis had commenced and had finished recruiting by January 2007.
Current opinion in investigational drugs (London, England: 2000) 12/2007; 8(11):947-54. · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Deletion of exon CD44v7 abrogates experimental colitis by apoptosis induction in intestinal mononuclear cells. Here we show that CD44v7 expression was upregulated upon CD40 ligation in human mononuclear cells, and examined whether ligation of CD44v7 also affects activation and apoptosis in lamina propria mononuclear cells (LPMC) from Crohn's disease (CD) patients. Thirty five patients with chronic inflammatory bowel disease (IBD), fourteen controls and four patients with diverticulitis were evaluated. CD44v7 was upregulated predominantly in the inflamed mucosa of CD patients. Furthermore, incubation with an anti-CD44v7 antibody induced apoptosis in LPMC isolated from inflamed mucosa of CD patients, but not from non-inflamed mucosa, from patients with ulcerative colitis (UC) or from normal controls. CD40 ligation and simultaneous incubation with anti-CD44v7 significantly downregulated CD80 in dendritic cells, thus inhibiting a critical second signal for naive T-cell activation. The apoptotic signal was mediated via the intrinsic mitochondrial pathway with decreased Bcl-2 and increased 7A6 (a mitochondrial membrane protein) expression. It was Fas independent and required caspases-3 and -9 activation. The process is highly specific for macrophage activation via CD40. These findings point to a novel mechanism of apoptosis induction in CD patients mediated by CD44v7 ligation.
Cell Death and Differentiation 09/2007; 14(8):1542-51. · 8.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Crohn's disease (CD) is a common, chronic, inflammatory bowel disease characterized by intestinal infiltration of activated immune cells and distortion of the intestinal architecture. In this study, we demonstrate that IL-22, a cytokine that is mainly produced by activated Th1 and Th17 cells, was present in high quantities in the blood of CD patients in contrast to IFN-gamma and IL-17. In a mouse colitis model, IL-22 mRNA expression was elevated predominantly in the inflamed intestine but also in the mesenteric lymph nodes. IL-22BP, the soluble receptor for IL-22, demonstrated an affinity to IL-22 that was at least 4-fold higher than its membrane-bound receptor, and its strong constitutive expression in the intestine and lymph nodes was decreased in the inflamed intestine. To investigate the possible role of systemic IL-22 in CD, we then administered IL-22 to healthy mice and found an up-regulation of LPS-binding protein (LBP) blood levels reaching concentrations known to neutralize LPS. This systemic up-regulation was associated with increased hepatic but not renal or pulmonary LBP mRNA levels. IL-22 also enhanced the secretion of LBP in human primary hepatocytes and HepG2 hepatoma cells in vitro. This increase was mainly transcriptionally regulated and synergistic with that of other LBP inducers. Finally, elevated LBP levels were detected in CD patients and the mouse colitis model. These data suggest that systemic IL-22 may contribute to the prevention of systemic inflammation provoked by LPS present in the blood of CD patients through its induction of hepatic LBP.
The Journal of Immunology 06/2007; 178(9):5973-81. · 5.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over the past several years, research in the field of cytokine production and function has become indispensable to understand the immunopathology of chronic intestinal inflammation. Thereupon, clinical studies analyzing cytokine production have generated a tremendous amount of data. In patients with inflammatory bowel disease, several studies examined pro-inflammatory cytokines in gut tissue and plasma, but a clear interpretation of the results with respect to disease activity or therapeutic response has been hampered by patient- and sample-related pitfalls.
International Journal of Colorectal Disease 10/2006; 21(6):505-7. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In patients with steroid-refractory Crohn's disease, the therapeutic goal is to achieve both rapid remission and maintenance of clinical response.
To evaluate the long-term benefit in patients treated with cyclophosphamide pulse therapy and azathioprine or methotrexate, a combination shown to be effective in a recent pilot study.
Sixteen patients with acute steroid-refractory Crohn's disease participated in a prospective open-labelled uncontrolled pilot study between December 1998 and June 2003. All had a median number of 4 monthly pulses of intravenous cyclophosphamide (750 mg) and were followed until relapse of the disease.
Thirteen of 16 patients (81%) achieved remission within 8 weeks after two pulses of cyclophosphamide in combination with azathioprine or methotrexate, with a Crohn's Disease Activity Index decrease from 294 to 111 (median). Remission sustained for 19 months (median, range: 1-45). Moreover, eight patients with pyoderma gangrenosum and erythema nodosum who responded to cyclophosphamide have maintained their remission for up to 30 months.
In steroid refractory patients with Crohn's disease, cyclophosphamide is highly effective to induce remission. This uncontrolled study indicates that cyclophosphamide-induced remission is long-lasting under standard immunosuppressive therapy.
[Show abstract][Hide abstract] ABSTRACT: Increased expression of CD44 variant isoforms have been shown on the inflammatory infiltrates in human and mouse colitis and blockade or deletion of CD44 isoforms inhibit experimental colitis. The objective of this study was to find out if short-term treatment of CD44 antibodies specific to CD44v7, but not to other variant isoforms, suppresses leucocyte-endothelial interaction in chronic dextran sodium sulphate (DSS)-induced colitis in mice. Chronic colitis was induced by oral administration of four cycles of 5% DSS in BALB/c mice. Expression of CD44 was investigated on isolated mononuclear cells of the gut immune system. In established colitis, mice were treated with antibodies against CD44v7 or CD44v4 three times in 7 days. Intravital microscopy was used to study leucocyte-endothelial interactions and leucocyte extravasation. As a marker of inflammatory infiltrates myeloperoxidase was quantified in gut tissue. CD44-induced apoptosis was determined by fluorescence staining of hypodiploidic cell nuclei. In chronic DSS-induced colitis both CD44 variant isoforms, v4 and v7 were significantly up-regulated on mononuclear cells. However, whereas anti-CD44v7 antibody treatment induced a marked restoration of the gut mucosa and significantly reduced endothelial sticking and extravasation of circulating leucocyte in vivo (P < 0.01), application of anti-CD44v4 or an isotype control antibody had no anti-inflammatory effect. A significant reduction of myeloperoxidase activity was detected after blockade of CD44v7, but not v4. Short-term treatment with anti-CD44v7 antibody blocks T cell extravasation and recruitment to the intestinal mucosa and cures established experimental colitis.
[Show abstract][Hide abstract] ABSTRACT: Collagen XIV (CXIV) is a fibril-associated collagen that is mainly expressed in well differentiated tissues and in late embryonic development. Because CXIV is almost absent in proliferating and/or dedifferentiated tissues, a functional role in maintaining cell differentiation is suspected. We demonstrate antiproliferative, quiescence- and differentiation-inducing effects of human CXIV and its recombinant fragments on mesenchymal cells. In primary human fibroblasts, in mouse 3T3 fibroblasts and in 3T3-L1 preadipocytes, CXIV reduced de novo DNA synthesis by 75%, whereas cell numbers and viability remained unaltered. Cells showed no signs of apoptosis, and maximal proliferation was restored when serum was supplemented, thus indicating that CXIV induced reversible cellular quiescence. Exposure of fibroblasts to CXIV in vitro led to cellular bundles and clusters. CXIV also triggered trans-differentiation of 3T3-L1 preadipocytes into adipocytes, as could be shown by lipid accumulation and by expression of the glucose transporter Glut4. These effects were also observed with the amino-terminal recombinant fragment Gln(29)-Pro(154) that harbors the first fibronectin type III domain and a 39-amino-acid extension, whereas no activity was found for all other recombinant CXIV fragments. Based on these finding the development of small molecular analogs that modulate fibroblast cell growth and differentiation, e.g. in wound healing and fibrosis, seems feasible.
Journal of Biological Chemistry 12/2005; 280(46):38537-43. · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role in the immune response in Crohn's disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation.
We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro.
Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10(-7) M, it acted as an IL-12 antagonist as it inhibited interferon gamma (IFN-gamma) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10(-6) M, IL-12(p40)-IgG2b increased IFN-gamma secretion and lymphocyte proliferation thereby acting as an IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor alpha, and increased IL-10 secretion.
The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: In normal conditions human gut mucosa is infiltrated with a large number of mononuclear cells due to continuous stimulation by luminal antigens. This state of "physiological" inflammation is tightly controlled, as several mucosal cells interact to maintain an appropriate local immune response. Moreover, gut-associated lymphoid tissue must constantly distinguish harmless antigens that are present in food and on commensal bacteria from pathogenic microbes. INTERVENTIONS AND RESEARCH: The oral administration of soluble protein antigens induces a state of systemic immunological unresponsiveness specific to the fed protein, termed oral tolerance. The two major mechanisms to explain oral tolerance are anergy/deletion of autoreactive lymphocytes and active suppression. Changes in the pathways of immune activation are detected in chronic intestinal inflammation, such as inflammatory bowel disease or celiac disease. CONCLUSION: An appreciation of the current knowledge of the gut immune system is of importance for understanding and development of new treatment modalities in chronic intestinal inflammation.
International Journal of Colorectal Disease 06/2003; 18(3):181-7. · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Overexpression of the cell adhesion protein CD44v6 has been demonstrated in colorectal cancer and other gastrointestinal tumors. While CD44v6 is upregulated in benign colorectal adenomas and well-differentiated colorectal cancer tissues, downregulation frequently occurs during disease progression. The mechanism of downregulation, however, is unknown. Therefore, we evaluated the methylation status of the CD44 promoter as a mechanism for decreased CD44v6 expression in advanced colorectal carcinomas. We demonstrated by methylation-sensitive restriction enzyme digestion that the CpG islands of the CD44 promoter were methylated in 6/21 (28%) of benign colorectal adenomas. Interestingly, in colorectal carcinomas the frequency of promoter methylation was significantly increased (10/19; 53%) compared to 7/21 (33%) in the corresponding normal mucosa. Methylation seems to be associated with a more advanced cancer stage, but the trend did not reach statistical significance. In colorectal carcinomas with CD44 promoter methylation CD44v6 mRNA was detected by reverse transcription-polymerase chain reaction in 3/10 carcinomas, whereas in tumors without CD44 promoter methylation CD44v6 expression was observed in 8/9 (P <or= 0.05). These results demonstrated that methylation of the 5'CpG island of the CD44 gene is closely associated with decreased expression of CD44v6 in human colorectal carcinomas.
Experimental and Molecular Pathology 06/2003; 74(3):262-6. · 2.13 Impact Factor