title: Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease.
abstract: Inflammatory bowel disease (IBD) arises from inappropriate activation of the mucosal immune system resulting in a state of chronic inflammation with causal links to colon cancer. Helicobacter hepaticus-infected Rag2(-/-) mice emulate many aspects of human IBD, and our recent work using this experimental model highlights the importance of neutrophils in the pathology of colitis. To define molecular mechanisms linking colitis to the identity of disease biomarkers, we performed a translational comparison of protein expression and protein damage products in tissues of mice and human IBD patients. Analysis in inflamed mouse colons identified the neutrophil- and macrophage-derived damage products 3-chlorotyrosine (Cl-Tyr) and 3-nitrotyrosine, both of which increased with disease duration. Analysis also revealed higher Cl-Tyr levels in colon relative to serum in patients with ulcerative colitis and Crohn disease. The DNA chlorination damage product, 5-chloro-2'-deoxycytidine, was quantified in diseased human colon samples and found to be present at levels similar to those in inflamed mouse colons. Multivariate analysis of these markers, together with serum proteins and cytokines, revealed a general signature of activated innate immunity in human IBD. Signatures in ulcerative colitis sera were strongly suggestive of neutrophil activity, and those in Crohn disease and mouse sera were suggestive of both macrophage and neutrophil activity. These data point to innate immunity as a major determinant of serum and tissue profiles and provide insight into IBD disease processes.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Knutson
authors.forename: Aswin
authors.initials: A
authors.lastname: Mangerich
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.forename: Arkadiusz R
authors.initials: AR
authors.lastname: Raczynski
authors.forename: Rosa G
authors.initials: RG
authors.lastname: Liberman
authors.forename: Pilsoo
authors.initials: P
authors.lastname: Kang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Ye
authors.forename: Erin G
authors.initials: EG
authors.lastname: Prestwich
authors.forename: Kun
authors.initials: K
authors.lastname: Lu
authors.forename: John S
authors.initials: JS
authors.lastname: Wishnok
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Korzenik
authors.forename: Gerald N
authors.initials: GN
authors.lastname: Wogan
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.forename: Peter C
authors.initials: PC
authors.lastname: Dedon
authors.forename: Steven R
authors.initials: SR
authors.lastname: Tannenbaum
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016481:Helicobacter Infections / Q000150:complications; D044923:Helicobacter hepaticus; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D003841:Deoxycytidine; C035826:5-chloro-2'-deoxycytidine; C002744:3-nitrotyrosine; D014443:Tyrosine; C087259:3-chlorotyrosine
keywords: granulocyte; myeloperoxidase; nitric oxide; oxidative stress