Loss of Protein Tyrosine Phosphatase Nonreceptor Type 22 Regulates Interferon-γ–Induced Signaling in Human Monocytes

MR Spalinger, S Lang, A Weber, P Frei, M Fried… - Gastroenterology, 2013 - Elsevier
MR Spalinger, S Lang, A Weber, P Frei, M Fried, G Rogler, M Scharl
Gastroenterology, 2013Elsevier
BACKGROUND & AIMS: A gain-of-function variation within the locus that encodes protein
tyrosine phosphatase nonreceptor type (PTPN) 22 is associated with a reduced risk for
Crohn's disease (CD), whereas a loss-of-function variant seems to promote autoimmune
disorders. We investigated how loss of PTPN22 could contribute to chronic inflammation of
the intestine. METHODS: Intestinal tissue samples from patients with or without inflammatory
bowel disease (controls) were analyzed for levels of PTPN22 messenger RNA (mRNA) and …
BACKGROUND & AIMS
A gain-of-function variation within the locus that encodes protein tyrosine phosphatase nonreceptor type (PTPN)22 is associated with a reduced risk for Crohn's disease (CD), whereas a loss-of-function variant seems to promote autoimmune disorders. We investigated how loss of PTPN22 could contribute to chronic inflammation of the intestine.
METHODS
Intestinal tissue samples from patients with or without inflammatory bowel disease (controls) were analyzed for levels of PTPN22 messenger RNA (mRNA) and protein. In human THP-1 monocytes, protein levels were analyzed by immunoblotting, mRNA levels by real-time polymerase chain reaction, and cytokine release by enzyme-linked immunosorbent assay.
RESULTS
Intestinal tissue samples from patients with CD had reduced levels of PTPN22 mRNA and protein, compared with samples from controls. In human THP-1 monocytes, interferon-γ (IFN-γ) induced expression and activity of PTPN22. Loss of PTPN22 increased levels of p38-mitogen-activated protein kinase, but reduced phosphorylation of nuclear factor-κB subunits. Increased activity of suppressor of cytokine signaling-1 was accompanied by reduced phosphorylation of signal-transducer and activator of transcription protein 1 and signal-transducer and activator of transcription protein 3 in PTPN22-deficient cells incubated with cytokines. PTPN22 knockdown increased secretion of the inflammatory cytokines interleukin (IL)-6 and IL-17, but reduced expression or secretion of T-bet, intercellular adhesion molecule-1, nucleotide-binding oligomerization domain containing-2, monocyte chemoattractant protein-1, IL-2, and IL-12p40 in response to IFN-γ.
CONCLUSIONS
PTPN22 expression is reduced in intestinal tissues of patients with active CD. PTPN22 regulates intracellular signaling events and is induced by IFN-γ in human monocytes. Knockdown of PTPN22 alters activation of inflammatory signal transducers, increasing secretion of T-helper 17–related inflammatory mediators. Genetic variants that reduce PTPN22 activity might contribute to the pathogenesis of CD by these mechanisms.
Elsevier