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1.
Inflamm Bowel Dis ; 19(7): 1463-9, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23598814

ABSTRACT

BACKGROUND: Dysmenorrhea and Crohn's disease (CD) have overlapping symptoms; however, their relationship is poorly understood. The aims of this study were to examine (1) the impact of dysmenorrhea on pain severity and pain medication use in CD and (2) the relationships between dysmenorrhea, CD activity, and health-related quality of life (HRQOL). METHODS: This was a case-control study of menstruating women with and without CD. Subjects were assessed for dysmenorrhea, pain severity, medication use, menstrual distress, and HRQOL. CD activity scores were calculated. The correlation between menstrual distress and CD activity was assessed. Linear regression analysis was performed to determine the effects of dysmenorrhea and CD on pain severity. RESULTS: A total of 110 subjects were studied and 40% of cases had dysmenorrhea. Dysmenorrhea was associated with higher pain scores among cases. Compared with controls, cases with dysmenorrhea reported similar pain severity but lower nonsteroidal anti-inflammatory drug use. After adjusting for medication use, cases had significantly greater distress due to menstrual pain. CD activity scores were not higher in women with dysmenorrhea; however, menstrual distress scores correlated positively with disease activity. HRQOL was significantly lower in cases with dysmenorrhea by some measures. CONCLUSIONS: Dysmenorrhea is common in women with CD and has an additive effect on overall pain severity. It is not, however, associated with greater nonsteroidal anti-inflammatory drug use. Menstrual distress is positively correlated with CD activity scores and associated with lower HRQOL by some measures. Treatment of dysmenorrhea may improve the pain experienced by women with CD, the perception of CD activity, and the quality of life in women with CD.


Subject(s)
Crohn Disease/complications , Dysmenorrhea/epidemiology , Menstruation , Pain/prevention & control , Quality of Life , Adaptation, Psychological , Adolescent , Adult , Case-Control Studies , Dysmenorrhea/etiology , Female , Follow-Up Studies , Humans , Middle Aged , Pain/etiology , Prevalence , Prognosis , Risk Factors , Severity of Illness Index , Young Adult
2.
Gut ; 62(4): 520-30, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22442160

ABSTRACT

OBJECTIVE: Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. DESIGN: Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk(-/-) mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. RESULTS: Using Ctsk(-/-) mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk(-/-) mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk(-/-) mice ameliorates the severity of intestinal inflammation. CONCLUSION: These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.


Subject(s)
Cathepsin K/pharmacology , Colitis/drug therapy , Colitis/microbiology , Animals , Blotting, Western , Cathepsin K/metabolism , Colitis/chemically induced , Colitis/pathology , Dextran Sulfate , Disease Models, Animal , Endoscopy, Gastrointestinal , Enzyme-Linked Immunosorbent Assay , Immunohistochemistry , Mice , Mice, Inbred C57BL , Real-Time Polymerase Chain Reaction
3.
J Immunol ; 184(12): 7247-56, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20483763

ABSTRACT

The expression of pathogen recognition receptors in human FOXP3+ T regulatory cells is established, yet the function of these receptors is currently obscure. In the process of studying the function of both peripheral and lamina propria FOXP3+ lymphocytes in patients with the human inflammatory bowel disease Crohn's disease, we observed a clear deficiency in the quantity of FOXP3+ lymphocytes in patients with disease-associated polymorphisms in the pathogen recognition receptor gene NOD2. Subsequently, we determined that the NOD2 ligand, muramyl dipeptide (MDP), activates NF-kappaB in primary human FOXP3+ T cells. This activation is functionally relevant, as MDP-stimulated human FOXP3+ T cells are protected from death receptor Fas-mediated apoptosis. Importantly, apoptosis protection was not evident in MDP-stimulated FOXP3+ T cells isolated from a patient with the disease-associated polymorphism. Thus, we propose that one function of pathogen recognition receptors in human T regulatory cells is the protection against death receptor-mediated apoptosis in a Fas ligand-rich environment, such as that of the inflamed intestinal subepithelial space.


Subject(s)
Apoptosis/immunology , Crohn Disease/immunology , Forkhead Transcription Factors/immunology , Nod2 Signaling Adaptor Protein/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Apoptosis/genetics , Blotting, Western , Cell Separation , Cell Survival , Crohn Disease/genetics , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Forkhead Transcription Factors/metabolism , Genotype , Humans , Immunohistochemistry , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Male , Middle Aged , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/metabolism , Polymorphism, Single Nucleotide , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolism , Transfection
4.
Inflamm Bowel Dis ; 16(2): 320-331, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19714745

ABSTRACT

BACKGROUND: Inflammatory bowel diseases (IBDs) result from environmental and genetic factors and are characterized by an imbalanced immune response in the gut and deregulated activation of the transcription factor NF-kappaB. Addressing the potential role of gly96/iex-1 in the regulation of NF-kappaB in IBD, we used the dextran sodium sulfate (DSS) colitis model in mice in which the gly96/iex-1 gene had been deleted. METHODS: C57BL/6 mice of gly96/iex-1(-/-) or gly96/iex-1(+/+) genotype were treated continuously with 4% DSS (5 days) and repeatedly with 2% DSS (28 days) for inducing acute and chronic colitis, respectively. In addition to clinical and histological exploration, colon organ culture and bone marrow-derived cells (BMCs) were analyzed for chemo/cytokine expression and NF-kappaB activation. RESULTS: Compared to wildtype littermates, gly96/iex-1(-/-) mice exhibited an aggravated phenotype of both acute and chronic colitis, along with a greater loss of body weight and colon length. Colonic endoscopy revealed a higher degree of hyperemia, edema, and bleeding in gly96/iex-1(-/-) mice, and immunohistochemistry detected massive mucosal infiltration of leukocytes and marked histological changes. The expression of proinflammatory chemo- and cytokines was higher in the colon of DSS-treated gly96/iex-1(-/-) mice, and the NF-kappaB activation was enhanced particularly in the distal colon. In cultured BMCs from gly96/iex-1(-/-) mice, Pam(3)Cys(4) treatment induced expression of proinflammatory mediators to a higher degree than in gly96/iex-1(+/+) BMCs, along with greater NF-kappaB activation. CONCLUSIONS: Based on the observation that genetic ablation of gly96/iex-1 triggers intestinal inflammation in mice, we demonstrate for the first time that gly96/iex-1 exerts strong antiinflammatory activity via its NF-kappaB-counterregulatory effect.


Subject(s)
Colitis/genetics , Immediate-Early Proteins/physiology , NF-kappa B/physiology , Animals , Chemokines/physiology , Colitis/pathology , Colitis/physiopathology , Colon/pathology , Cytokines/physiology , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Immediate-Early Proteins/genetics , Macrophages/physiology , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Neutrophils/physiology , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/physiology
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