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

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 ( trans -desensitization). 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.

Elevated SOCS3 and altered IL-6 signaling is associated with age-related human muscle stem cell dysfunction

“…A delay in the induction of IL-6 in the SCs was in contrast to the whole muscle and systemic response, which was more rapid (significant increases at 3 h in both mRNA and serum) and more robust compared with the young controls. This may be partially explained by the elevated basal SOCS3 in the muscle, which may have desensitized the SCs to IL-6 (20,62). The muscle stem cell niche is sensitive to age-related alterations in signaling molecules (15,23) and thus chronically elevated muscle IL-6 (as demonstrated at the mRNA level) may have negatively impacted the microenvironment of the SCs, impairing normal IL-6 signaling.…”

IL-6 is required for glioma development in a mouse model

“…Under normal conditions, IL-6-mediated STAT3 activation is transient and continuous stimulation does not lead to permanent STAT3 activation (Fischer et al, 2003). Inactivation of IL-6-induced feedback inhibitors like SOCS1 and SOCS3 by hypermethylation might come into play.…”

IL-27 Activates Human Monocytes via STAT1 and Suppresses IL-10 Production but the Inflammatory Functions of IL-27 Are Abrogated by TLRs and p38

“…7B); the time frame of these experiments is short, such that the LPS-mediated induction of CXCL9 and CXCL10 that occurs indirectly via autocrine IFN-␤ is not readily detectable. The IL-27 receptor is comprised of gp130 and WSX-1 subunits (13), and we and others have shown that gp130-mediated signaling is strongly inhibited by TLRs via a rapidly induced mechanism that is dependent on p38 and independent of de novo protein synthesis (45)(46)(47)(48)(49)(50)(51). Interestingly, inhibition of IL-27 signaling was induced rapidly, within 30 min of TLR stimulation (Fig.…”