Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling

Biochem J. 2001 Jan 1;353(Pt 1):109-116.

Abstract

Interleukin 9 (IL-9) is a cytokine preferentially produced by T helper type 2 lymphocytes and active on various cell types such as T- and B-lymphocytes, mast cells and haemopoietic progenitors. The IL-9 receptor (IL-9R) belongs to the haemopoietic receptor superfamily and its signal transduction involves mainly the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Here we studied the implication of a novel family of suppressors of cytokine signalling (called CIS, for cytokine-inducible SH2-containing protein, and SOCS, for suppressor of cytokine signalling) in IL-9 signal attenuation. In BW5147 T-cell lymphoma, IL-9 induced the rapid expression of CIS, SOCS-2 and SOCS-3 with a peak after 2 h of stimulation. Using IL-9R mutants, we showed that STAT activation is required for CIS/SOCS induction: CIS and SOCS-2 expression was induced either via STAT1 and/or STAT3 or via STAT5 but only STAT1 and/or STAT3 were involved in SOCS-3 expression. The effect of these three proteins on IL-9 signal transduction was assessed by transient transfection in HEK-293 cells expressing the components of the IL-9 signalling pathway and a STAT-responsive reporter construct. These experiments showed that only SOCS-3 is able to inhibit IL-9-induced signal transduction; neither CIS nor SOCS-2 exerted any effect. Stable transfection of CIS and SOCS-3 in BW5147 lymphoma cells showed that only overexpression of SOCS-3 had an inhibitory activity on STAT activation, gene induction and the anti-apoptotic activity of IL-9. By contrast, CIS failed to affect the IL-9 response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Feedback / drug effects
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Interleukin-9 / antagonists & inhibitors*
  • Interleukin-9 / pharmacology*
  • Janus Kinase 1
  • Milk Proteins*
  • Mutation
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Interleukin / antagonists & inhibitors
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-9
  • Repressor Proteins*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Signal Transduction / drug effects*
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism
  • Transcription Factors*
  • Transfection
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • IL9R protein, human
  • Immediate-Early Proteins
  • Interleukin-9
  • Milk Proteins
  • Proteins
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-9
  • Repressor Proteins
  • SOCS2 protein, human
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • cytokine inducible SH2-containing protein
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1