title: Loss of protein tyrosine phosphatase nonreceptor type 22 regulates interferon-γ-induced signaling in human monocytes.
abstract: OBJECTIVE
  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.
authors: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors: Marianne R
authors: MR
authors: Spalinger
authors: Silvia
authors: S
authors: Lang
authors: Achim
authors: A
authors: Weber
authors: Pascal
authors: P
authors: Frei
authors: Michael
authors: M
authors: Fried
authors: Gerhard
authors: G
authors: Rogler
authors: Michael
authors: M
authors: Scharl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002450:Cell Communication; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D011994:Recombinant Proteins; C554125:interferon gamma-1b; D007371:Interferon-gamma; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22