257 Discussion In this study, we show that increased fecal calprotectin levels – a broadly applied marker for the assessment of disease activity in CD patients – highly significantly correlate with elevated serum IFN-γ and CRP levels. Moreover, significant correlations were observed between serum levels of IL-6, IL-17A, TNF-β and SAA and fecal calprotectin levels. These findings indicate that identification of biomarker profiles might serve as an additional approach to determine inflammatory disease activity in CD patients. Our data not only provide correlations between fecal calprotectin levels and inflammatory markers in the systemic circulation, but also confirm that Th1 responses are important in CD patients with active disease since IFN-γ levels were significantly elevated, as well as serum TNF-α levels, although the latter did not reach statistical significance. Furthermore, an interesting additional finding is the borderline non-significant enhancement of serum IL-17A levels (P = 0.058) in CD patients with increased fecal calprotectin levels. IL-17A has been shown to be a driving effector response for colitis in mice. However, transfer of T-cells from IL-17-deficient mice induced severe colitis in mice recipients and enhanced IFN-γ-producing T-cells.20 Likewise, in humans, it is less clear whether IL-17 has a protective role or induces an effector response.21,22 In our study, we found elevated IL-17A levels specifically in CD patients with increased fecal calprotectin levels, suggesting that it is a marker for inflammatory disease activity instead of a protective marker. Interestingly, we also found that the Th17-stimulating cytokines IL-6 and TNF-β were enhanced in the group with increased fecal calprotectin levels, further supporting that an activated Th17 response is involved in these patients in addition to the Th1 response. Our findings on the association between C-reactive protein (CRP) and fecal calprotectin levels corroborate the findings of other studies.23,24 CRP is an acute-phase protein, mainly produced by hepatocytes in response to systemic inflammation. Production occurs after stimulation by IL-6, IL-1β and TNF-α. In clinical practice, CRP is used as a general biomarker for inflammation and is therefore commonly applied to monitor the disease course of CD. CRP rapidly increases after an acute-phase stimulus and has a short half-life, making CRP an useful marker for acute inflammatory events in CD.25 In CD, active disease is significantly associated with both elevated CRP and fecal calprotectin levels.14,26 Elevated CRP levels at diagnosis are predictive for the requirement of future surgical interventions in CD and therefore for disease severity.27 Also, increased CRP levels prior to treatment with the TNF-α-antagonist infliximab were predictive of a higher response rate and treatment success.25,28 Additionally, our data demonstrate that enhanced serum CRP levels correlate with inflammatory disease activity, as it was specifically enhanced in the CD patient group with increased fecal calprotectin levels. In the present study, serum IFN-γ levels were significantly elevated in CD patients with increased fecal calprotectin levels, as compared to patients with remissive disease. Likewise, it has previously been observed that circulating IFN-γ levels are strongly increased in IBD patients as opposed to healthy subjects.29 IFN-γ is known for its central role in the Th1-driven immune response, which constitutes the major signaling pathway in the pathogenesis of CD.15 IFN-γ is predominantly produced by Th1-differentiated T-cells residing in the intestinal lamina propria upon stimulation by IL-12-producing macrophages in the nearby environment.30 Therefore, since we observe a strong correlation between fecal calprotectin levels and serum IFN-γ, this Inflammatory proteins in Crohn’s disease
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