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P040. Protein tyrosine phosphate non receptor type 22 regulates muramyl-dipeptide induced effects in human monocytes

M. Scharl1, M. Spalinger1, S. Lang1, A. Weber2, S. Vavricka1, P. Frei1, M. Fried1, G. Rogler1, 1University Hospital Zürich, Division of Gastroenterology and Hepatology, Zürich, Switzerland, 2University Hospital Zürich, Institute for Surgical Pathology, Zürich, Switzerland


Recent studies demonstrated that a gain-of-function variant within the gene locus encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) protects from Crohn's disease (CD). We have recently shown that interferon-γ (IFN γ) induces PTPN22 expression and activity and PTPN22, in turn, controls IFN γ-induced signaling, gene expression and cytokine secretion in human monocytes. The aim of this study was to investigate, whether PTPN22 regulates the response to the bacterial wall component, muramyl-dipeptide (MDP) in human THP-1 monocytes.


Intestinal biopsies were obtained from non-IBD control patients, patients with active CD or active ulcerative colitis (UC). Protein analysis was performed by Western blotting, mRNA levels were measured by real-time PCR and cytokine release by ELISA. PTPN22 knock-down was induced in THP-1 monocytes by siRNA.


In intestinal tissue samples from non-IBD control patients, strong staining for PTPN22 co-localized with cell-type specific markers, mainly CD68 (macrophages/monocytes), but also CD3 (T-cells), CD20 (B-cells) and CD56 (NK-cells). Though PTPN22 staining in CD and UC patients with active disease was clearly reduced, we could still detect some PTPN22 co-localization with CD3 and CD20 in IBD patients, while almost no co-staining was detectable in CD68 and CD56 positive cells. In THP-1 monocytes, PTPN22 mRNA and protein levels were reduced by interleukin (IL)-1β and TNF, but increased by IL-6 and IL-23 in response to MDP treatment for up to 48 h. Interestingly, the bacterial wall component, MDP (500 ng/ml), induced PTPN22 mRNA (p < 0.01), protein level (p < 0.05) and phosphatase activity (p < 0.01) by 24 h treatment. Loss of PTPN22 further enhanced MDP-induced phosphorylation of c-Jun N-terminal kinase (JNK; p < 0.001) and p38 (p < 0.001) as well as of the NF κB-isoforms, p65 (p < 0.05) and p50 (p < 0.05) by 30 min treatment. On a functional level, PTPN22 knock-down resulted in further increased secretion of IL-6 (p < 0.01) and IL-8 (p < 0.001) after 24 h MDP treatment. Of note, loss of PTPN22 already increased basal secretion of IL-6 (p < 0.05) and IL-8 (p < 0.05).


PTPN22 expression is reduced in intestinal monocytes/macrophages in patients with active CD. Knock-down of PTPN22 in human monocytes promotes activation of inflammatory signal transducers resulting in enhanced secretion of pro-inflammatory mediators in response to MDP. Our data explain how reduced PTPN22 activity could contribute to the pathogenesis of CD.