Perpetuation Of Chronic Intestinal Inflammation Research Articles

P009 IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells

Abstract Background The pathogenesis of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) is still incompletely understood. However, despite having been described back in the 1980s and reported to be involved in chronic inflammatory arthritis, the role of interleukin 3 (IL-3) signaling via the IL-3 receptor (IL-3R) in the development and perpetuation of chronic intestinal inflammation remains largely unexplored. In this study, we therefore aimed to explore the role of IL-3 signaling via IL-3R in experimental colitis as well as human IBD. Methods We analysed IL-3 expression in lamina propria mononuclear cells (LPMCs) from patients with IBD and from mice with experimental colitis. We compared the development of T cell transfer colitis in Rag1-/- mice after transfer of Il3r-/- and Il3r+/+ naïve T cells and investigated the underlying mechanisms by immunofluorescence and functional cell trafficking assays. The mechanical properties of Il3r-/- and Il3r+/+ T cells were determined by real-time deformability cytometry (RT-DC) and atomic force microscopy (AFM) and cytoskeleton structure was analysed by scanning electron microscopy (SEM) and fluorescence recovery after photobleaching (FRAP). Results The expression of IL-3 and IL3+ T cells were increased in the gut of patients with IBD and IL-3 expression was associated to shorter flare-free survival. In vivo, experimental chronic colitis upon T cell transfer was exacerbated in the absence of IL-3 or IL-3R signalling. This was attributable to IL-3-induced changes in kinase signalling and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of regulatory T (Treg) cells from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Treg cells. (A) IL3 mRNA expression in colon tissue from patients.(B) Flare-free survival of IBD patients.(C) Colitis in Rag1–/– mice after transfer of naïve CD4+ T cells from Il3r+/+ and Il3r-/- mice. Mini-endoscopy (left) and IVIS (right).(D) RT-DC plot (left) and quantification (right) of thymic lymphocytes from Il3r-/- and Il3r+/+ mice.(E) Lightsheet microscopy (left) and quantification of TReg index (right, TReg fraction in Ozanimod/DATK32 per fraction in placebo) in mLNs from Rag1-/- mice with transfer colitis induced by Il3r-/- or Il3r+/+ T cells. Conclusion We uncover a crucial role of IL-3R signalling in regulating TReg mechanobiology and tissue egress. Together, our data demonstrate a central – probably counter-regulatory – role for IL-3 receptor signalling in Treg cells in the pathogenesis of murine and human chronic intestinal inflammation and therefore suggest that IL-3 might be a novel target for future therapeutic approaches in IBD.

P052 Comparing T cell responses to food antigens in Inflammatory Bowel Disease patients and healthy donors

Abstract Background The role of nutrition in Inflammatory Bowel Disease (IBD) remains unclear. Studies about the effects of nutritional components on intestinal inflammation and the gut microbiome, as well as the concept of exclusive enteral nutrition in paediatric Crohn’s Disease (CD) are suggestive of an impact of nutrition on the pathophysiology. However, there is currently a lack of knowledge on how food components may affect IBD. Here, we investigated the T helper (Th) cell response against nutritional antigens in healthy controls and IBD patients. Methods We used a highly sensitive and specific method developed in our lab, the antigen reactive T cell enrichment (ARTE), to detect wheat and milk-reactive CD4+ T cells directly ex vivo in blood of healthy controls (n=18), CD (n=17) and Ulcerative Colitis (UC, n=15) patients. Peripheral blood mononuclear cells (PBMC) were incubated with whole antigen lysates and activated T helper cells were identified based on the up-regulation of the activation marker CD154. Magnetic enrichment of CD154 positive cells enabled to collect sufficient numbers of food-reactive T cells for their detailed characterization by multiparameter flow cytometry. Results We detected low frequencies of milk and wheat-reactive T cells in healthy individuals. Milk-reactive T cells were less frequent and expressed several markers of T cell exhaustion. In CD, but not UC patients, we identified higher frequencies of food-reactive T cells. These tended to be particularly increased in patients with disease manifestation in the upper gastrointestinal tract. In addition, we observed increased production of inflammatory cytokines of wheat-reactive T cells in CD, compared to healthy controls and UC patients. No ground-breaking differences were identified regarding the expression of exhaustion markers between IBD patients and controls. Conclusion Frequencies of food-reactive Th cells are increased in CD and show a proinflammatory cytokine pattern. The Th1-response of wheat-reactive T cells, characterized by high IFN-γ-secretion, might contribute to the perpetuation of chronic intestinal inflammation.

IL-33 attenuates development and perpetuation of chronic intestinal inflammation

Interleukin-33 (IL-33) is a member of the IL-1 family. Recent evidence shows the importance of IL-33 in autoimmune and inflammatory diseases. To elucidate its impact on inflammatory bowel disease we studied the effects of exogenous IL-33 during the induction of acute dextran sodium sulfate (DSS)-induced colitis, the induction period of chronic DSS colitis, and after establishment of chronic inflammation. For induction of acute colitis mice received DSS in their drinking water for 7 days and were killed at day 8 or 14 after first DSS administration. Chronic colitis was induced by four cycles of DSS. Animals were treated with IL-33 between the DSS cycles (intermediate treatment) or after onset of chronic disease (posttreatment). Colons and mesenteric lymph nodes were isolated for histology and cytokine secretion, flow cytometric analysis, determination of myeloperoxidase, and transcription factor activity. While IL-33 in acute colitis led to slight aggravation of inflammation, both chronic colitis approaches resulted in a significant reduction of inflammatory colon contraction, amelioration of disease scores, suppression of interferon-gamma (IFN-γ), and a shift to T helper (Th)2-associated cytokines. Examination of colon tissue revealed increased Ly6g-mRNA levels and myeloperoxidase (MPO) activity in IL-33-treated animals. Evaluation of bacterial translocation revealed decreased translocation incidence in IL-33-treated mice. In summary, IL-33 has extenuating effects in chronic DSS-induced colitis: Excessive Th1-directed cytokine responses are shifted toward Th2-like immune reactions and general inflammation parameters are reduced. IL-33-induced neutrophil influx during chronic inflammation reduced translocation of pathogenic bacteria across damaged epithelium.

Protein Tyrosine Phosphatase Nonreceptor Type 2 Regulates Autophagosome Formation in Human Intestinal Cells

Autophagy is a process of central importance for maintaining cell homeostasis, survival, and the regulation of inflammation. Recent studies associated variants within the gene loci, encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2), and autophagy genes, such as autophagy-related 16-like 1 (ATG16L1), with chronic inflammatory disorders, such as Crohn's disease (CD). We show that PTPN2 regulates autophagy in human intestinal epithelial cells (IEC) and primary colonic lamina propria fibroblasts (CLPF). Protein analysis in IEC and CLPF was performed by western blotting. Autophagososme formation was assessed by LC3B immunofluorescence or immunohistochemistry. Human intestinal tissue samples were obtained from noninflammatory bowel disease (IBD) control or from CD patients and genotyped for disease-associated PTPN2 or ATG16L1 variations. Knockdown of PTPN2 causes impaired autophagosome formation and dysfunctional autophagy resulted in increased levels of intracellular Listeria monocytogenes (LM) and elevated IEC apoptosis in response to tumor necrosis factor (TNF) and interferon gamma (IFN-γ). Similar findings were observed in primary CLPF derived from CD patients carrying the CD-associated PTPN2 variant. Presence of the ATG16L1 variant prevented the cytokine-induced rise in PTPN2 protein, finally resulting in impaired LC3B-II levels in IEC. Actively inflamed intestinal biopsies from CD patients carrying either ATG16L1 or PTPN2 genetic variants revealed aberrant LC3B expression patterns when compared with samples from non-IBD control patients. Our results demonstrate that PTPN2 regulates autophagosome formation in human intestinal cells. We provide a model of how a dysfunction of the CD susceptibility genes, PTPN2 and/or ATG16L1, may contribute to the onset and perpetuation of chronic intestinal inflammation.

M1796 TGF-Alpha Autocrine Signaling is a Key Step in TNF-Alpha-Stimulated Proinflammatory Signaling in Intestinal Epithelial Cells

1) play an important role in the pathophysiology of CD. The aim of this study was to demonstrate a role for PTPN2 in the regulation of IFNγ-induced signalling and cytokine production in THP-1 monocytic cells. Methods: Protein analysis was performed by Western blotting, PTPN2 knock-down was induced by siRNA and cytokine levels were measured by ELISA. Results: We demonstrated that IFNγ (1000 U/ml) treatment of THP-1 cells elevates PTPN2 protein reaching a peak by 24 h (p<0.05; n=6). Increased PTPN2 expression, in turn, correlates with decreased activity of the important IFNγ-signalling molecules, signal transducer and activator of transcription (STAT) 1 and STAT3. Knock-down of PTPN2 by siRNA potentiated IFNγ-induced (24 h) phosphorylation of STAT1 (p<0.001; n=4) and STAT3 (p<0.05; n=4), respectively. Further, while loss of PTPN2 also enhanced the phosphorylation of the mitogen-activated protein kinase (MAPK) family member, p38 (p<0.05; n=4), it did not affect phosphorylation of the MAPK-isoforms, extracellular signal regulated protein kinase 1/2 (ERK1/2; n=4) or c-Jun N-terminal kinase (JNK; n=4). As a functional consequence, PTPN2 knock-down potentiated IFNγ-induced secretion of the proinflammatory cytokines IL-6 (p<0.01; n=3) and MCP-1 (p<0.001; n=4). Conclusions: In summary, our data demonstrate that IFNγ treatment enhances PTPN2 protein in THP-1 cells while loss of PTPN2 potentiates IFNγ-induced activation of downstream signalling intermediates and secretion of IL6 and MCP-1 proinflammatory cytokines. These findings support the hypothesis that dysfunction of PTPN2 exacerbates inflammation-related events in a cell model of inflammation, and loss of PTPN2 activity could thus play a significant role in the onset as well as the perpetuation of chronic intestinal inflammation, such as CD. The study was supported by CCFA, DFG, SNF and an educational grant by Essex Chemie, Switzerland.

Inflammatory Bowel Diseases: When Natural Friends Turn into Enemies—The Importance of CpG Motifs of Bacterial DNA in Intestinal Homeostasis and Chronic Intestinal Inflammation

From numerous studies during the last years it became evident that bacteria and bacterial constituents play a decisive role both in the maintenance of intestinal immune homeostasis as well as in the development and perpetuation of chronic intestinal inflammation. In this review we focus on the role of bacterial DNA which is a potent immunomodulatory component of the bacterial flora. Bacterial DNA has been shown to be protective against experimental colitis. In contrast bacterial DNA essentially contributes to the perpetuation of an already established chronic intestinal inflammation in a Toll-like receptor (TLR)9-dependent manner. This dichotomic action may be explained by a different activation status of essential regulators of TLR signaling like Glycogen synthase kinase 3-β (GSK3-β) depending on the pre-activation status of the intestinal immune system. In this review we suggest that regulators of TLR signaling may be interesting therapeutic targets in IBD aiming at the restoration of intestinal immune homeostasis.

Effect of Azithromycin on Acute Inflammatory Lesions and Colonic Bacterial Load in a Murine Model of Experimental Colitis

The aim of this study was to investigate the effect of the macrolide antibiotic azithromycin on mucosal changes and colonic bacterial load in a murine model of colitis. Colitis was induced in CD1 mice using enema of 0.2% solution of dinitrofluorobenzene, combined with skin sensitization. Four experimental groups of animals (N = 10 per group) were treated with 50 mg/kg/day azithromycin (AZ) or metronidazole (MN) perorally, starting 24 h before (AZ-1, MN-1) or 6 h after (AZ+1, MN+1) induction of colitis and for consecutive 5 days. Additional experimental mice group was treated with 10 mg/kg/day methylprednisolone intraperitoneally after induction of experimental colitis in the same manner (MP). Two control groups consisted of healthy animals (C) that received the challenge enema with phosphate-buffered saline (PBS) and animals with experimental colitis (chall) treated with equivolume of PBS perorally. Clinical score (0-5) and histopathologic score (0-30) were used to assess inflammatory changes, and colon washings were used to determine changes in bacterial load. The anti-inflammatory effect of azithromycin did not differ from the effect of methylprednisolone, when compared with control group with experimental colitis. Metronidazole did not show a significant anti-inflammatory effect. Number of colonic bacteria did not differ significantly between control and experimental groups of animals. We documented the anti-inflammatory effect of azithromycin in a murine model of acute colitis, suggesting that effects were targeted to oxidative burst and on mucosal/bacterial interface, independent of luminal bacterial load. Further studies should be focused on effect of azithromycin on the role of bacterial biofilm in perpetuation of chronic intestinal inflammation.

Cytokine association with bacterial DNA in serum of patients with inflammatory bowel disease

The pathogenesis of inflammatory bowel disease (IBD) involves the interaction between genetic susceptibility, mucosal immunity, and intestinal bacteria. Bacterial translocation is a common event in these patients and plays an important role in the perpetuation of chronic intestinal inflammation. Blood microbiological cultures, however, are frequently negative. The aim was to evaluate the presence of bacterial DNA (bactDNA) and the associated cytokine response in patients with IBD. Fifteen healthy donors, 29 patients with ulcerative colitis (UC), and 33 patients with Crohn's disease (CD) were studied. The presence of bactDNA was pursued by PCR followed by nucleotide sequencing analysis. Microbiological cultures were carried out among all controls and patients. Cytokine serum levels were measured by enzyme-linked immunosorbent assay (ELISA). BactDNA was detected in 14 out of 33 patients with CD (42.4%) and in 15 out of 29 patients with UC (51.7%). BactDNA translocation was present in 7 out of 21 (33%) and in 10 out of 15 (34%) patients with CD and UC in remission, respectively. None of healthy controls showed bactDNA in serum. A statistically significant increase in all Th1-derived cytokines in CD but not in UC patients with the presence of bactDNA was observed in comparison with patients without bactDNA and controls. BactDNA is present in IBD patients, irrespective of their disease activity. This fact is associated with a marked Th1-driven immune reaction in CD patients, even in those in remission. Whether bactDNA is inducing or is favored by an increased inflammatory scenario in these patients remains under discussion.

Preliminary study on bacterial translocation in serum of patients with inflammatory bowel disease

The pathogenesis of inflammatory bowel disease (IBD) involves the interaction between genetic susceptibility, mucosal immunity and intestinal bacteria. Bacterial DNA (bact DNA) derived from luminal bacteria may contribute to the perpetuation of chronic intestinal inflammation. Blood microbiological cultures, though, are frequently negative in these patients and bacterial translocation episodes may be put out of sight. To evaluate the presence of bacterial translocation in patients with IBD by means of detection of bacterial DNA in blood. 23 patients with IBD not treated with antibiotics the month before inclusion were considered in the study and distributed into the following groups: Group I: active Crohn's disease (CD); Group II: inactive CD; Group III: active ulcerative colitis (UC); and Group IV: inactive UC. A blood sample was collected in endotoxin-freetubes and a broad-range PCR of a highly conserved region of the bacterial 16SrRNA gene was performed using the following primers: 5′-TTCCGGTTGATC-CTGCCGGA-3′ as forward, and 5′-GGTTACCTTGTTACGACTT-3′ as reverse. Bacterial genomic fragments were purified (QIAquick, QIAgen) and identified by automated nucleotide sequencing analysis (ABIPRISM 310, Applied Biosystems). Sequence alignments were carried out with NCBI database (www.ncbi.nih.gov), using the advanced BLAST search tool. Microbiological cultures were carried out among all the patients. the number of patients studied and the percentage of patients with bacterial DNA are detailed in Table 1, according to previously mentioned group distribution. Bacteria identifications included E. coli, Enterococcus spp and Staphylococcus spp. Blood cultures were negative in all cases. Molecular detection tools in patients with IBD are able to identify a subgroup of patients with presence of circulating bacterial DNA that remain undetected by microbiological culture. The presence of bacterial translocation in patients with inactive CD, the surprising prevalence of bacterial DNA from Enterococcus spp in patients with active UC, and the likely existence of immune consequences associated to these facts require new investigations.

Differential Protein Expression Profile in the Intestinal Epithelium from Patients with Inflammatory Bowel Disease

The loss of intestinal epithelial cell (IEC) function is a critical component in the initiation and perpetuation of chronic intestinal inflammation in the genetically susceptible host. We applied proteome analysis (PA) to characterize changes in the protein expression profile of primary IEC from patients with Crohn's disease (CD) and ulcerative colitis (UC). Surgical specimens from 18 patients with active CD (N = 6), UC (N = 6), and colonic cancer (N = 6) were used to purify primary IEC from ileal and colonic tissues. Changes in protein expression were identified using 2D-gel electrophoreses (2D SDS-PAGE) and peptide mass fingerprinting via MALDI-TOF mass spectrometry (MS) as well as Western blot analysis. PA of primary IEC from inflamed ileal tissue of CD patients and colonic tissue of UC patients identified 21 protein spots with at least 2-fold changes in steady-state expression levels compared to the noninflamed tissue of control patients. Statistical significance was achieved for 9 proteins including the Rho-GDP dissociation inhibitor alpha that was up-regulated in CD and UC patients. Additionally, 40 proteins with significantly altered expression levels were identified in IEC from inflamed compared to noninflamed tissue regions of single UC (N = 2) patients. The most significant change was detected for programmed cell death protein 8 (7.4-fold increase) and annexin 2A (7.7-fold increase). PA in primary IEC from IBD patients revealed significant expression changes of proteins that are associated with signal transduction, stress response as well as energy metabolism. The induction of Rho GDI alpha expression may be associated with the destruction of IEC homeostasis under condition of chronic intestinal inflammation.

CpG Motifs of Bacterial DNA Essentially Contribute to the Perpetuation of Chronic Intestinal Inflammation

Recently, we demonstrated a proinflammatory effect of cytosin-guanosin dinucleotide (CpG)-oligodeoxynucleotide (ODN) treatment in established dextran sulphate sodium (DSS)-induced colitis. Here, we investigated whether DNA derived from luminal bacteria plays a role in the perpetuation of chronic intestinal inflammation. Toll-like receptor (TLR9)-deficient and wild-type (wt) control mice were used for the induction of chronic DSS colitis. Moreover, mice with established chronic colitis using different experimental models were treated with adenoviral ODN (AV-ODN) known to block CpG effects. Colonic inflammation was scored and cytokine production was quantified both in colonic tissue and draining mesenteral lymph node cells (MLC). Eight weeks after induction of chronic DSS colitis in TLR9-deficient mice, intestinal inflammation was significantly lower (-68%), and proinflammatory cytokine production was drastically reduced. Treatment of wt mice with chronic DSS-induced colitis with AV-ODN resulted in a significant amelioration of disease with a reduced histologic score (-43%) and reduced cytokine production of MLC (interleukin [IL]-6: -68%; interferon [IFN]-gamma: -48%) and RNA expression of the T helper (Th)1-specific transcription factor T-bet (-62%) in colonic tissue. Qualitatively, the same results were obtained in the severe combined immunodeficiency disease (SCID) transfer model of colitis and in spontaneous colitis in IL-10-deficient mice. Bacterial DNA derived from luminal bacteria contributes significantly to the perpetuation of chronic intestinal inflammation. Inhibition of the immune-stimulating properties of bacterial DNA using AV-ODN may offer a novel and specific tool for the treatment of inflammatory bowel disease.

Involvement of IL-6 in the Pathogenesis of Inflammatory Bowel Disease and Colon Cancer

Inflammatory bowel disease (IBD), which consists of Crohn's disease and ulcerative colitis, is defined as a chronic inflammation of the gastrointestinal tract. The etiopathogenetic mechanisms underlying the development of IBD are still not completely understood, and the therapeutic strategies used thus far have been limited to mostly evidence-based principles. There is growing evidence that the pro-inflammatory cytokine interleukin (IL)-6 plays a crucial part in the uncontrolled intestinal inflammatory process, which is a main characteristic of IBD. There is elevated production of IL-6 and its soluble receptor (sIL-6R) by intestinal macrophages and CD4+T-cells. The increased formation of IL-6-sIL-6R complexes that interact with gp130 on the membrane of CD4+T-cells (trans-signaling) lead to an increased expression and nuclear translocation of STAT3, which causes the induction of anti-apoptotic genes, such as Bcl-xl. This leads to an augmented resistance of lamina propria T-cells to apoptosis. The ensuing T-cell expansion contributes to the perpetuation of chronic intestinal inflammation. This understanding concerning the predominant pathogenic role of an IL-6-dependent inflammatory cascade may lead to the development of new therapeutic strategies in the treatment of this disease. Recent studies have also suggested a potential role of IL-6-sIL-6R in the pathogenesis of colon cancer and, therefore, imply a possible novel therapeutic strategy targeting the sIL-6R and ensuing IL-6 trans-signaling.

Immune networks in animal models of inflammatory bowel disease.

The animal models of inflammatory bowel disease provide a framework to define the immunopathogenesis of intestinal inflammation. Studies in these models support the hypothesis that exaggerated immune responses to normal enteric microflora are involved in the initiation and perpetuation of chronic intestinal inflammation. A major pathway involves development of acquired immune responses by the interactions of CD4+ T-cell receptor alphabeta T cells with antigen-presenting cells (dendritic cells). Immunoregulatory cells, including Tr1 cells, Th3 cells, and CD4+ CD25+ T cells and B cells, directly or indirectly affect the T-cell receptor alphabeta T cell-induced immune responses and bridge innate and acquired immunity. The study of these complicated immune networks provides the rationale for the development of new therapeutic interventions in inflammatory bowel disease.

CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice.

Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal immune response with elevated levels of the Th1 cytokines TNF, IL-12 and IFN-gamma. The luminal flora has been implicated as a major factor contributing to the initiation and perpetuation of chronic intestinal inflammation by as yet unknown mechanisms. Bacterial DNA contains unmethylated cytosine-guanosine dinucleotides (CpG) which strongly activate Th1-mediated immune responses. To test whether these CpG-motifs contribute to intestinal inflammation we treated mice with dextran-sulfate-sodium (DSS)-induced acute or chronic colitis for 5 days with CpG-containing oligodeoxynucleotides (CpG-ODN). Colonic inflammation was assessed by histological scoring. Colonic cytokine RNA was quantified by reverse transcription-PCR and cytokine secretion from mesenterial lymph node cells by ELISA. In chronic colitis, CpG-ODN treatment severely aggravated inflammation by 50%. Colonic expression of IFN-gamma and TNF was elevated (200- and 150-fold, respectively) and IFN-gamma and IL-12 secretion from lymph node cells was increased 5,000- and 8-fold, respectively, compared to GpG-ODN-treated controls. Similar effects were obtained in acute colitis. In conclusion, CpG-motifs of bacterial DNA have proinflammatory activity by strengthening the Th1 arm of immunity in DSS-induced colitis, and might therefore play a significant role in the initiation and perpetuation of inflammation in IBD.

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo.

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.

A role for transcription factor NF-kappa B in intestinal inflammation.

Nuclear factor (NF) kappa B is a transcription factor that controls the transcription of a variety of cellular genes regulating the inflammatory response. Many proinflammatory cytokines are transcriptionally regulated by NF-kappa B, and their increased expression has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Even though it seemed clear that the increase in proinflammatory cytokine production in IBD is crucial for the initiation and perpetuation of chronic intestinal inflammation, the elements governing this dysregulation of enhanced cytokine production remained unclear. This review discusses a series of recent studies that demonstrate the activation of NF-kappa B in the inflamed mucosa, and that shed new light on the central pathogenic role of NF-kappa B in chronic intestinal inflammation. In addition to describing the activation of NF-kappa B, excitement has been generated by reports that define the molecular targets of anti-inflammatory agents, and that demonstrate the effective blockade of NF-kappa B in intestinal inflammation. These new insights into the activation and inhibition of NF-kappa B have opened new and promising avenues for a more specific treatment of chronic intestinal inflammation.