Crohn’s Disease and Ulcerative Colitis Show Unique Cytokine Profiles

Introduction Networks of cytokines have been implicated in both forms of inflammatory bowel disease (IBD): Crohn’s disease (CD) and ulcerative colitis (UC). While CD has associated with T-helper type 1 (Th1) immune responses, UC shows Th2 patterns. Recent studies reported that the inflamed intestinal regions in both CD and UC are significantly infiltrated with a newly described set of T helper, the Th17 cells. These cells have unique cytokine responses. These findings prompted us to further explore the cytokine profiles of CD and UC with a special focus on the Th2 and Th17 related mediators. Methods Cytokine transcripts were compared using real-time polymerase chain reaction (PCR) in both inflamed and non-inflamed mucosal specimens from patients with active CD (n=35) or UC (n=20) and without CD or UC (Control, n=54). Results In both CD and UC, interleukin (IL)-12 (p40), IL-18, IL-21 and IL-27 transcript levels were higher than in Control. The highest levels of cytokines were found in the diseased areas of CD and UC with only one exception; IL-12 (p40) in CD was more up-regulated in the non-diseased areas compared to diseased CD and Control specimens. CD samples but not UC specimens showed significant IL-17, IL-23, and IL-32 mRNA expression indicating a trend toward Th17 responses. In UC, however, IL-5, IL-13, IL-15 and IL-33 mRNA levels were significantly increased when compared to both CD and Control. Conclusions The unique patterns of cytokine networks can help us to better understand the differential expression of their characteristic pathophysiology. In addition, the pharmacological regulation of these small molecules may hold promise to more effective and personalized therapies.

[1]  B. Molnár,et al.  Changes of the cytokine profile in inflammatory bowel diseases. , 2012, World journal of gastroenterology.

[2]  D. Wolf,et al.  Community Perspectives: Combining Serology, Genetics, and Inflammation Markers for the Diagnosis of IBD and Differentiation Between CD and UC. , 2012, Gastroenterology & hepatology.

[3]  H. Hammad,et al.  Cellular networks controlling Th2 polarization in allergy and immunity , 2012, F1000 biology reports.

[4]  R. Giannella,et al.  Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease , 2012, Expert review of clinical immunology.

[5]  E. Szigethy,et al.  Inflammatory bowel disease. , 2011, Pediatric clinics of North America.

[6]  T. Macdonald,et al.  IL‐23/IL‐17 axis in IBD , 2010, Inflammatory bowel diseases.

[7]  C. Fiocchi,et al.  Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis , 2010, Proceedings of the National Academy of Sciences.

[8]  R. Blumberg Inflammation in the Intestinal Tract: Pathogenesis and Treatment , 2009, Digestive Diseases.

[9]  D. Bernardo,et al.  High Levels of Proinflammatory Cytokines, but Not Markers of Tissue Injury, in Unaffected Intestinal Areas from Patients with IBD , 2009, Mediators of inflammation.

[10]  T. Giese,et al.  Transcript levels of different cytokines and chemokines correlate with clinical and endoscopic activity in ulcerative colitis , 2009, BMC gastroenterology.

[11]  S. Targan,et al.  Recent advances in IBD pathogenesis: Genetics and immunobiology , 2008, Current gastroenterology reports.

[12]  K. Maloy The Interleukin‐23 / Interleukin‐17 axis in intestinal inflammation , 2008, Journal of internal medicine.

[13]  B. Müller-Myhsok,et al.  Role of the novel Th17 cytokine IL‐17F in inflammatory bowel disease (IBD): Upregulated colonic IL‐17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD , 2008, Inflammatory bowel diseases.

[14]  A. Rizzo,et al.  Regulation of gut inflammation and th17 cell response by interleukin-21. , 2008, Gastroenterology.

[15]  J. Yamamoto-Furusho,et al.  Novel genetic markers in inflammatory bowel disease. , 2007, World journal of gastroenterology.

[16]  T. Macdonald,et al.  New players in the cytokine orchestra of inflammatory bowel disease , 2007, Inflammatory bowel diseases.

[17]  J. Kolls,et al.  After interleukin-12p40, are interleukin-23 and interleukin-17 the next therapeutic targets for inflammatory bowel disease? , 2007, International immunopharmacology.

[18]  J. A. Garrote,et al.  The pattern of cytokine expression determines the degree of mucosal damage , 2007, Gut.

[19]  T. Hansson,et al.  Fecal levels of leukocyte markers reflect disease activity in patients with ulcerative colitis , 2007, Scandinavian journal of clinical and laboratory investigation.

[20]  R. Burakoff,et al.  Use of antibiotics in the treatment of inflammatory bowel disease , 2006, Inflammatory bowel diseases.

[21]  M. Vander Vliet,et al.  A phase 1/2A Trial of STA 5326, an oral interleukin‐12/23 inhibitor, in patients with active moderate to severe Crohn's disease , 2006, Inflammatory bowel diseases.

[22]  R. Sartor Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis , 2006, Nature Clinical Practice Gastroenterology &Hepatology.

[23]  J. Satsangi,et al.  The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications , 2006, Gut.

[24]  Thomas Lengauer,et al.  Dissection of the Inflammatory Bowel Disease Transcriptome Using Genome-Wide cDNA Microarrays , 2005, PLoS medicine.

[25]  S. Targan,et al.  Bacterial flagellin is a dominant antigen in Crohn disease. , 2004, The Journal of clinical investigation.

[26]  T. Giese,et al.  Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn’s disease , 2004, International Journal of Colorectal Disease.

[27]  G. Bouma,et al.  The immunological and genetic basis of inflammatory bowel disease , 2003, Nature Reviews Immunology.

[28]  A. Andoh,et al.  Increased expression of interleukin 17 in inflammatory bowel disease , 2003, Gut.

[29]  T. Giese,et al.  Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's disease , 2002, Virchows Archiv.

[30]  R. Sartor Induction of mucosal immune responses by bacteria and bacterial components. , 2001, Current opinion in gastroenterology.

[31]  A. Kornbluth,et al.  Immunomodulator therapy in inflammatory bowel disease , 2001, Current treatment options in gastroenterology.

[32]  B. Vainer,et al.  Established and emerging biological activity markers of inflammatory bowel disease. , 2000, The American journal of gastroenterology.

[33]  S. Hanauer,et al.  Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. , 1999, Inflammatory bowel diseases.

[34]  P. Reitsma,et al.  Five genetic markers in the interleukin 1 family in relation to inflammatory bowel disease , 1998, Gut.

[35]  J. Reimund,et al.  Increased production of tumour necrosis factor-alpha interleukin-1 beta, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn's disease. , 1996, Gut.

[36]  A. Kruse,et al.  Cytokine expression in intestinal mucosal biopsies. In situ hybridisation of the mRNA for interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha in inflammatory bowel disease. , 1994, European cytokine network.

[37]  R. Sartor,et al.  Cytokines in intestinal inflammation: pathophysiological and clinical considerations. , 1994, Gastroenterology.

[38]  M. Kagnoff Immunology of the intestinal tract. , 1993, Gastroenterology.

[39]  S. Haskill,et al.  Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. , 1992, Gastroenterology.