E elucidated.AcknowledgmentsWe are grateful to Dr George Baillie for the

E elucidated.AcknowledgmentsWe are grateful to Dr George Baillie for the use of the ECL imager system.Author ContributionsConceived and designed the experiments: FL AA KH. Performed the experiments: AA. Analyzed the data: FL AA. Contributed reagents/ materials/analysis tools: AA FL. Wrote the paper: FL AA.
Crohn’s Disease (CD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract. The etiopathogenesis of CD is not fully understood, but genetic and environmental factors interact to promote an excessive and poorly controlled mucosal inflammatory response directed against components of the gut microflora. [1?] Functional abnormalities of many components of the immune system can be seen in the damaged gut of CD patients, but hyperactivity of T cells with excessive production of inflammatory cytokines is believed to be one of the major immunological hallmarks of this disorder. CD-associated destructive immune response is polarized along the T helper (Th)1 cell pathway, as indicated by the demonstration that mucosal CD4+T cells produce large quantities of interferon (IFN)-c [3] and overexpress T-bet, a transcription factor necessary for driving and sustaining Th1 cell responses. [4] CD DBeQ tissue also contains high interleukin (IL)-12, [5] the major Th1-inducing factor in humans, [6] and IL-18, a cytokine that expands Th1 cell responses. [7] Despite these observations and the demonstration that Th1-typecytokines are pro-inflammatory 18325633 in murine models of CD, [8] blockade of IFN-c with a neutralizing antibody (i.e. Fontolizumab) was not beneficial in CD patients. [9?0] These disappointing results could rely on the fact that the CD-associated tissue lesions are driven by multiple and disconnected inflammatory pathways, which are not fully inhibited by Fontolizumab. Indeed, the inflamed gut of CD patients is also massively infiltrated with a distinct subset of Th cells, termed Th17 cells, which over-express the transcription factors retinoic acid-related orphan receptor (ROR)-ct and RORa, produce IL-17A, IL-17F, IL-21, IL-22, and IL-26, and are negatively regulated by IFN-c. [11?4] Even the administration of a neutralizing IL-17A antibody was not effective in CD, thus confirming the complexity of the tissue-damaging immunoinflammatory events in CD. [15] Data emerging from 10457188 recent studies raise the possibility that the mucosal cytokine profile in CD is not stable and may vary with the course of the disease thus contributing to the lack of therapeutic response to cytokine blockers. For example, analysis of T cell-derived cytokines in supernatants of T cell clones derived from intestinal biopsies ofDistinct Cytokine Patterns in CDchildren with CD and stimulated with IL-12 revealed that IFN-c levels were markedly elevated in patients with first attack of CD but not in those with established lesions. [16] Moreover some of the IL-17A-producing cells infiltrating CD tissue co-express IFN-c and can lack IL-17A and be converted into Th1 cells following stimulation with IL-12. [17] In CD, deviation from a Th17 to a Th1 Dimethyloxallyl Glycine phenotype could be favoured not only by high IL-12 but also defects in TGF-b1 activity due to high Smad7, an intracellular inhibitor of TGF-b1-driven signalling, because TGF-b1 is needed to sustain IL-17A production by Th17 cells [18?1]. Altogether these observations indicate that better understanding of the cytokines temporally regulated in CD tissue is needed to identify optimal targets for therapeutic interventions. The aim.E elucidated.AcknowledgmentsWe are grateful to Dr George Baillie for the use of the ECL imager system.Author ContributionsConceived and designed the experiments: FL AA KH. Performed the experiments: AA. Analyzed the data: FL AA. Contributed reagents/ materials/analysis tools: AA FL. Wrote the paper: FL AA.
Crohn’s Disease (CD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract. The etiopathogenesis of CD is not fully understood, but genetic and environmental factors interact to promote an excessive and poorly controlled mucosal inflammatory response directed against components of the gut microflora. [1?] Functional abnormalities of many components of the immune system can be seen in the damaged gut of CD patients, but hyperactivity of T cells with excessive production of inflammatory cytokines is believed to be one of the major immunological hallmarks of this disorder. CD-associated destructive immune response is polarized along the T helper (Th)1 cell pathway, as indicated by the demonstration that mucosal CD4+T cells produce large quantities of interferon (IFN)-c [3] and overexpress T-bet, a transcription factor necessary for driving and sustaining Th1 cell responses. [4] CD tissue also contains high interleukin (IL)-12, [5] the major Th1-inducing factor in humans, [6] and IL-18, a cytokine that expands Th1 cell responses. [7] Despite these observations and the demonstration that Th1-typecytokines are pro-inflammatory 18325633 in murine models of CD, [8] blockade of IFN-c with a neutralizing antibody (i.e. Fontolizumab) was not beneficial in CD patients. [9?0] These disappointing results could rely on the fact that the CD-associated tissue lesions are driven by multiple and disconnected inflammatory pathways, which are not fully inhibited by Fontolizumab. Indeed, the inflamed gut of CD patients is also massively infiltrated with a distinct subset of Th cells, termed Th17 cells, which over-express the transcription factors retinoic acid-related orphan receptor (ROR)-ct and RORa, produce IL-17A, IL-17F, IL-21, IL-22, and IL-26, and are negatively regulated by IFN-c. [11?4] Even the administration of a neutralizing IL-17A antibody was not effective in CD, thus confirming the complexity of the tissue-damaging immunoinflammatory events in CD. [15] Data emerging from 10457188 recent studies raise the possibility that the mucosal cytokine profile in CD is not stable and may vary with the course of the disease thus contributing to the lack of therapeutic response to cytokine blockers. For example, analysis of T cell-derived cytokines in supernatants of T cell clones derived from intestinal biopsies ofDistinct Cytokine Patterns in CDchildren with CD and stimulated with IL-12 revealed that IFN-c levels were markedly elevated in patients with first attack of CD but not in those with established lesions. [16] Moreover some of the IL-17A-producing cells infiltrating CD tissue co-express IFN-c and can lack IL-17A and be converted into Th1 cells following stimulation with IL-12. [17] In CD, deviation from a Th17 to a Th1 phenotype could be favoured not only by high IL-12 but also defects in TGF-b1 activity due to high Smad7, an intracellular inhibitor of TGF-b1-driven signalling, because TGF-b1 is needed to sustain IL-17A production by Th17 cells [18?1]. Altogether these observations indicate that better understanding of the cytokines temporally regulated in CD tissue is needed to identify optimal targets for therapeutic interventions. The aim.