The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling

Patrick Fischer, Ute Lehmann, Radoslaw M. Sobota, Jochen Schmitz, Claudia Niemand, Sonja Linnemann, Serge Haan, Iris Behrmann, Akihiko Yoshimura, James A. Johnston, Gerhard Müller-Newen, Peter C. Heinrich, Fred Schaper

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Abstract

The immediate early response of cells treated with IL-6 (interleukin-6) is the activation of the signal transducer and activator of transcription (STAT)3. The Src homology domain 2 (SH2)-containing protein tyrosine phosphatase SHP2 and the feedback inhibitor SOCS3 (suppressor of cytokine signalling) are potent inhibitors of IL-6 signal transduction. Impaired function of SOCS3 or SHP2 leads to enhanced and prolonged IL-6 signalling. The inhibitory function of both proteins depends on their recruitment to the tyrosine motif 759 within glycoprotein gp130. In contrast to inactivation, desensitization of signal transduction is regarded as impaired responsiveness due to prestimulation. Usually, after activation the sensing receptor becomes inactivated by modifications such as phosphorylation, internalization or degradation. We designed an experimental approach which allows discrimination between desensitization and inactivation of IL-6 signal transduction. We observed that pre-stimulation with IL-6 renders cells less sensitive to further stimulation with IL-6. After several hours, the cells become sensitive again. We show that not only signal transduction through previously activated receptors is affected by desensitization but signalling through receptors which were not targeted by the first stimulation was also attenuated (transdesensitization). Interestingly, in contrast to inhibition, desensitization does not depend on the presence of functional SHP2. Furthermore, cells lacking SOCS3 show constitutive STAT3 activation which is not affected by pre-stimulation with IL-6. All these observations suggest that desensitization and inhibition of signalling are mechanistically distinct.

Original languageEnglish
Pages (from-to)449-460
Number of pages12
JournalBiochemical Journal
Volume378
Issue number2
DOIs
Publication statusPublished - 2004 Mar 1
Externally publishedYes

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Keywords

  • Inflammation
  • Interleukin-6
  • Signal transducer and activator of transcription 3 (STAT3)
  • Signal transduction
  • Src homology domain 2-containing protein tyrosine phosphatase (SHP2)
  • Suppressor of cytokine signalling 3 (SOCS3)

ASJC Scopus subject areas

  • Biochemistry

Cite this

Fischer, P., Lehmann, U., Sobota, R. M., Schmitz, J., Niemand, C., Linnemann, S., Haan, S., Behrmann, I., Yoshimura, A., Johnston, J. A., Müller-Newen, G., Heinrich, P. C., & Schaper, F. (2004). The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling. Biochemical Journal, 378(2), 449-460. https://doi.org/10.1042/BJ20030893