Interleukin-34 Stimulates Gut Fibroblasts to Produce Collagen Synthesis

Author:

Franzè Eleonora1,Dinallo Vincenzo1,Laudisi Federica1,Di Grazia Antonio1,Di Fusco Davide1,Colantoni Alfredo1,Ortenzi Angela1,Giuffrida Paolo2,Di Carlo Sara3,Sica Giuseppe S3,Di Sabatino Antonio2,Monteleone Giovanni1

Affiliation:

1. Department of Systems Medicine, University of Rome ‘TOR VERGATA’, Rome, Italy

2. Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy

3. Department of Surgery, University ‘TOR VERGATA’ of Rome, Rome, Italy

Abstract

AbstractBackground and AimThe mechanisms underlying the formation of intestinal fibrostrictures [FS] in Crohn’s disease [CD] are not fully understood, but activation of fibroblasts and excessive collagen deposition are supposed to contribute to the development of FS. Here we investigated whether interleukin-34 [IL-34], a cytokine that is over-produced in CD, regulates collagen production by gut fibroblastsMethodsIL-34 and its receptor macrophage colony-stimulating factor receptor 1 [M-CSFR-1] were evaluated in inflammatory [I], FS CD, and control [CTR] ileal mucosal samples by real-time polymerase chain reaction [RT-PCR], western blotting, and immunohistochemistry. IL-34 and M-CSFR-1 expression was evaluated in normal and FS CD fibroblasts. Control fibroblasts were stimulated with IL-34 in the presence or absence of a MAP kinase p38 inhibitor, and FS CD fibroblasts were cultured with a specific IL-34 antisense oligonucleotide, and collagen production was evaluated by RT-PCR, western blotting, and Sircol assay. The effect of IL-34 on the wound healing capacity of fibroblasts was evaluated by scratch test.ResultsWe showed enhanced M-CSFR-1 and IL-34 RNA and protein expression in FS CD mucosal samples as compared with ICD and CTR samples. Immunohistochemical analysis showed that stromal cells were positive for M-CSFR-1 and IL-34. Enhanced M-CSFR-1 and IL-34 RNA and protein expression was seen in FS CD fibroblasts as compared with CTR. Stimulation of control fibroblasts with IL-34 enhanced COL1A1 and COL3A1 expression and secretion of collagen through a p38 MAP kinase-dependent mechanism, and wound healing. IL-34 knockdown in FS CD fibroblasts was associated with reduced collagen production and wound repair.ConclusionsData indicate a prominent role of IL-34 in the control of intestinal fibrogenesis.

Publisher

Oxford University Press (OUP)

Subject

Gastroenterology,General Medicine

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