Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21

Abstract

Background: T cell-mediated immunity plays a central part in the pathogenesis of tissue damage in inflammatory bowel disease (IBD). The mechanism by which T cells mediate tissue damage during IBD remains unclear, but evidence indicates that T cell-derived cytokines stimulate fibroblasts to synthesise matrix metalloproteinases (MMPs), which then mediate mucosal degradation. We have previously shown that, in IBD, there is high production of interleukin (IL) 21, a T cell-derived cytokine, which enhances Th1 activity. Aim: To investigate whether IL21 controls MMP production by intestinal fibroblasts. Methods: IL21 receptor (IL21R) was evaluated in intestinal fibroblasts by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. Fibroblasts were stimulated with IL21 and MMPs were evaluated by RT-PCR and western blotting. The effect of a neutralising IL21R fusion protein (IL21R/Fc) on the induction of MMPs in fibroblasts stimulated with IBD lamina propria mononuclear cell (LPMC) supernatants was also evaluated. Results: Intestinal fibroblasts constitutively express both IL21R and the common c chain receptor, which are necessary for IL21-driven signalling. IL21 enhances fibroblast production of MMP-1, MMP-2, MMP-3 and MMP-9, but not tissue inhibitors of MMP-1 and MMP-2. Moreover, IL21 synergises with tumour necrosis factor a to increase synthesis of MMP synthesis. IL21 enhances MMP secretion without affecting gene transcription and protein synthesis. IBD LPMC supernatants stimulate MMP secretion by intestinal fibroblasts, and this effect is partly inhibited by IL21R/Fc. Conclusions: These results suggest that fibroblasts are a potential target of IL21 in the gut and that IL21 controls MMP secretion by fibroblasts.

The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease

“…The behaviour of C3 mRNA expression in the IBD mucosa was different from other factors described previously [4,45,46]. Elevation of C3 mRNA expression was observed not only in active IBD mucosa but also in infectious colitis, although many factors have been reported to be elevated specifically in IBD mucosa [4,[45][46][47]. This suggests that C3 biosynthesis may be dependent upon molecular mechanisms specific and non-specific for IBD, as complements are major factors in innate immune responses against a huge number of antigens.…”

“…This suggests that C3 biosynthesis may be dependent upon molecular mechanisms specific and non-specific for IBD, as complements are major factors in innate immune responses against a huge number of antigens. An increasing number of studies have focused upon the role of Th17 cells in the pathogenesis of IBD [8,10,[12][13][14]47], due to its unique differentiation processes under the stimulus of transforming growth factor (TGF)-b and IL-6 [3][4][5][6][7][8][9][10][11]. Th17 cells develop from naive T lymphocytes through distinct pathways from classical Th1 and Th2 cells.…”

IL-21 comes of age as a regulator of effector T cells in the gut

“…An imbalance between MMPs and their inhibitors results during inflammation, implicating that inflammatory We have recently demonstrated that IL-21R is expressed by gut fibroblasts and that IL-21 stimulation results in the enhanced secretion of MMP-1, MMP-2, MMP-3, and MMP-9 but not tissue inhibitors of metalloproteinases. 49 Neutralization of IL-21 markedly reduces the amounts of MMPs released when fibroblasts are cultured with CD lamina propria mononuclear cell supernatants, confirming the role of IL-21 as mediator of the MMP-mediated tissue damage ( Figure 2 ). Interestingly, IL-21 does not affect the expression of MMPs at the transcriptional or post-transcriptional level, rather it acts by causing the release of intracellular stores of MMPs.…”

Cerebrospinal Fluid IL-21 Levels in Neuromyelitis Optica and Multiple Sclerosis

“…Soon after, a functional cloning approach identified a four-helix-bundle cytokine with structural relation to interleukin (Il)-2, Il-4 and Il-15 as the natural ligand to this receptor, naming the new entities Il-21 13 . The Il-21 receptor (Il-21R) is widely expressed, indicating a broad range of actions of Il-21 14,15 . Il-21/Il-21R regulates activation, proliferation and survival of both CD4 + T cells and B cells, and limits the differentiation of inducible Tregs and counteracts their suppressive properties on effector T cells 16 , both of which are involved in the pathogenesis of NMO and MS. Il-21 now has also been reported to contribute to the development of Th17 cells, and Th17 cells can produce Il-21, acting in an autocrine manner to amplify its own synthesis.…”