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.
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 humanTHP-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 humanTHP-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.
Authors: Yeniley Ruiz-Noa; Jorge Hernández-Bello; Mara A Llamas-Covarrubias; Claudia A Palafox-Sánchez; Edith Oregon-Romero; Pedro Ernesto Sánchez-Hernández; Maria Guadalupe Ramírez-Dueñas; Isela Parra-Rojas; Jose Francisco Muñoz-Valle Journal: J Clin Lab Anal Date: 2018-11-06 Impact factor: 2.352
Authors: Marianne R Spalinger; Thomas Sb Schmidt; Marlene Schwarzfischer; Larissa Hering; Kirstin Atrott; Silvia Lang; Claudia Gottier; Annelies Geirnaert; Christophe Lacroix; Xuezhi Dai; David J Rawlings; Andrew C Chan; Christian von Mering; Gerhard Rogler; Michael Scharl Journal: J Clin Invest Date: 2019-05-20 Impact factor: 14.808
Authors: Marianne R Spalinger; Stephanie Kasper; Claudia Gottier; Silvia Lang; Kirstin Atrott; Stephan R Vavricka; Sylvie Scharl; Tina Raselli; Isabelle Frey-Wagner; Petrus M Gutte; Markus G Grütter; Hans-Dietmar Beer; Emmanuel Contassot; Andrew C Chan; Xuezhi Dai; David J Rawlings; Florian Mair; Burkhard Becher; Werner Falk; Michael Fried; Gerhard Rogler; Michael Scharl Journal: J Clin Invest Date: 2016-04-04 Impact factor: 14.808