The cytokine network in inflammatory bowel disease (IBD) is a complex, dynamic system that plays an important role in regulating mucosal innate and adaptive immune responses. While several studies have been done to evaluate immunomodulatory profiles in murine IBD, they have been limited to a relatively small number of cytokines that do not take into account its dependency of the interplay of multiple factors, and therefore the diagnostic potential of their cytokine profiles have been inconclusive. Herein we demonstrate a novel approach of comprehensive serum multiplex cytokine profiling to describe the modulation of 16 Th1, Th2, Th17 cytokines and chemokines in both acute and chronic murine models of DSS and TNBS-induced colitis. Distinctive disease-specific cytokine profiles were identified with significant correlations to disease activity and duration of disease. TNBS colitis exhibits heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic. In contrast, DSS colitis switches from a Th1-Th17-mediated acute inflammation (increased TNFα, IL6, IL-17 and KC) to a predominant Th2-mediated inflammatory response (increase in IL-4 and IL-10 and concomitant decrease in TNFα, IL6, IL-17 and KC) in the chronic state. Profiles of multiple cytokines seen systemically were also validated locally in colonic mucosa. Moreover, advanced multivariate analyses identified discriminatory cytokine profiles that can be sufficiently used to distinguish unaffected controls from diseases, and one disease type from another. IL-6 and IL-12 stratified gender-associated disease activity in chronic colitis. Our studies provide insight into disease immunopathogenesis and illustrate the significant potential of utilizing multiplex cytokine profiles and bioinformatics as diagnostic tools in IBD.
Background & Aims
One of the most common symptoms among patients with inflammatory bowel diseases (IBD) is diarrhea, which is thought to be contributed by changes in electrolyte transport associated with intestinal inflammation. This study is designed to test the hypothesis that intestinal Na+-related transporters/channels and their regulatory proteins may be down-regulated as a potential contributor to IBD-associated diarrhea.
Methods
SDS-PAGE and Western blotting and/or confocal immunomicroscopy were used to examine the expression of Na+/H+-exchangers 1-3 (NHE1-3), epithelial Na+ channel (ENaC), Na+/K+-ATPase, the intracellular Cl- channel 5 (ClC-5), and NHE3 regulatory factors (NHERF1 & 2), in ileal and colonic pinch biopsies from IBD patients and noninflammatory controls, as well as from colonic mucosa of DSS- and TNBS-induced acute murine IBD models.
Results
NHE1&3 (but not NHE2), β-ENaC, Na+/K+-ATPase-α, ClC-5 and NHERF1 were all down-regulated in sigmoid mucosal biopsies from most cases of active UC and/or CD, compared to controls. NHE3 was also decreased in ileal mucosal biopsies of active CD, as well as in ~50% of sigmoid biopsies from inactive UC or CD. Importantly, similar down-regulation of NHE1&3, β-ENaC, and NHERF1&2 was also observed in the mouse colon (but not ileum) of DSS- and TNBS-induced colitis.
Conclusions
IBD-associated diarrhea may be due to a coordinated down regulation of multiple Na+ transporter and related regulatory proteins, including NHE1&3, Na+/K+-ATPase, and ENaC, as well as NHERF1 & 2, and ClC-5, all of which are involved directly or indirectly in intestinal Na+ absorption.
Plasma cytokines play an important role in the pathogenesis of Sjögren's syndrome (SS) by initiating and perpetuating various cellular and humoural autoimmune processes. The aim of the present study was to describe a broad spectrum of T-cell and B-cell cytokines, growth factors, chemokines and molecules that could contribute to cell death in SS. A novel protein array system was utilized to measure simultaneously the levels of 25 plasma cytokines of patients with primary SS and healthy individuals. Furthermore, we correlated these plasma cytokine levels with potential laboratory and clinical parameters related to disease activity in SS. A subset of plasma cytokines [e.g. interleukin-1b (IL-1b),
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