Loss of protein tyrosine phosphatase nonreceptor type 22 regulates interferon-γ-induced signaling in human monocytes.

Abstract

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.

• Authors: Marianne R Spalinger, Silvia Lang, Achim Weber, Pascal Frei, Michael Fried, Gerhard Rogler, Michael Scharl
• Journal: Gastroenterology (Gastroenterology) Vol. 144 Issue 5 Pg. 978-988.e10 (May 2013) ISSN: 1528-0012 [Electronic] United States
• PMID: 23380085 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• RNA, Messenger
• Recombinant Proteins
• interferon gamma-1b
• Interferon-gamma
• PTPN22 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 22

Topics

• Adolescent
• Adult
• Aged
• Cell Communication
• Crohn Disease (genetics, metabolism, pathology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Gene Expression Regulation
• Humans
• Immunoblotting
• Interferon-gamma (pharmacology)
• Intestine, Small (drug effects, metabolism, pathology)
• Male
• Middle Aged
• Monocytes (drug effects, metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 22 (genetics, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Real-Time Polymerase Chain Reaction
• Recombinant Proteins (pharmacology)
• Signal Transduction (genetics)
• Young Adult