Cutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells

Briso, Eva M.; Dienz, Oliver; Rincón, Mercedes

doi:10.4049/jimmunol.180.11.7102

Cited by 145 publications

(135 citation statements)

References 29 publications

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“…2D, pan T cell activation led to a temporal downregulation in IL-6R expression, which was paralleled by an increase in sIL-6R levels in culture supernatants. Such activationinduced loss of IL-6R was also evident in human T cell cultures (data not shown), as previously reported by Briso et al (15). Hence, infiltrating effector T cells shed IL-6R as a consequence of TCR engagement.…”

Section: Inflammatory Regulation Of Il-6r Expression On Murine T Cellssupporting

confidence: 70%

“…However, many of these activities are also directly associated with the action of IL-6 itself (10)(11)(12)(13)(14). Collectively, these data suggest that not all T cells express IL-6R or that T cell activation leads to a modulation in IL-6R expression (6,(15)(16)(17). Ultimately, these findings infer that classical IL-6R signaling and IL-6 trans signaling may regulate IL-6 responsiveness in T cells.…”

mentioning

confidence: 60%

“…Furthermore, in our study, SES-induced peritoneal inflammation resulted in the emergence of activated Th cells (CD4 + CD44 hi CD62L lo ) displaying significantly reduced levels of surface IL-6R expression. In this respect, T cell activation is linked with a marked downregulation in CD62L and IL-6R (15,39). Although the functional significance of these changes remains to be clarified, the processing of CD62L has been associated with an alteration in the proliferation and effector characteristics of Th1 and Th2 cells (39).…”

Section: Discussionmentioning

confidence: 99%

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Loss of CD4+ T Cell IL-6R Expression during Inflammation Underlines a Role for IL-6TransSignaling in the Local Maintenance of Th17 Cells

Jones

McLoughlin

Hammond

et al. 2010

The Journal of Immunology

163

138

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IL-6 responses are classically orchestrated via a membrane-bound IL-6R (CD126) α subunit (classical IL-6R signaling) or through a soluble form of this cognate receptor (IL-6 trans signaling). Appraisal of IL-6R expression on human and mouse T cells emphasized that IL-6R expression is closely linked with that of CCR7 and CD62L. In this regard, infiltrating effector T cells from clinical and experimental peritonitis episodes lose IL-6R expression, and anti-CD3/CD28 Ab costimulation of peripheral T cells in vitro leads to a downregulation in IL-6R expression. Consequently, IL-6 signaling through membrane-bound IL-6R seems to be limited to naive or central memory T cell populations. Loss of IL-6R expression by activated T cells further suggests that these effector cells might still retain IL-6 responsiveness via IL-6 trans signaling. Using IL-6R–deficient mice and recombinant tools that modulate the capacity of IL-6 to signal via its soluble receptor, we report that local control of IL-6 trans signaling regulates the effector characteristics of the T cell infiltrate and promotes the maintenance of IL-17A–secreting CD4+ T cells. Therefore, we concluded that classical IL-6R signaling in naive or central memory CD4+ T cells is required to steer their effector characteristics, whereas local regulation of soluble IL-6R activity might serve to maintain the cytokine profile of the Th cell infiltrate. Therefore, the activation status of a T cell population is linked with an alteration in IL-6 responsiveness.

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Section: Inflammatory Regulation Of Il-6r Expression On Murine T Cellssupporting

confidence: 70%

mentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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Loss of CD4+ T Cell IL-6R Expression during Inflammation Underlines a Role for IL-6TransSignaling in the Local Maintenance of Th17 Cells

Jones

McLoughlin

Hammond

et al. 2010

The Journal of Immunology

163

138

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“…Shedding of mIL-6Ra by ADAM10 and ADAM17 has been identified as a general mechanism of sIL-6Ra generation in mice (51), and it is very likely that shedding is responsible for the loss of IL-6Ra surface expression following L. monocytogenes infection. TCR triggering has been described as a signal for IL6Ra shedding (52,53); however, the global loss of IL-6Ra on naive and effector cells argues against a specific TCR signal at this early stage of infection. It is more likely that loss of IL-6Ra expression is due to shedding induced by inflammatory mediators such as proinflammatory cytokines, chemokines, or acute phase proteins (52,53).…”

Section: Discussionmentioning

confidence: 99%

IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

Hoge

Yan

Jänner

et al. 2013

The Journal of Immunology

127

107

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The cytokine IL-6 plays a protective role in immune responses against bacterial infections. However, the mechanisms of IL-6–mediated protection are only partially understood. IL-6 can signal via the IL-6R complex composed of membrane-bound IL-6Rα (mIL-6Rα) and gp130. Owing to the restricted expression of mIL-6Rα, classical IL-6 signaling occurs only in a limited number of cells such as hepatocytes and certain leukocyte subsets. IL-6 also interacts with soluble IL-6Rα proteins and these IL-6/soluble IL-6Rα complexes can subsequently bind to membrane-bound gp130 proteins and induce signaling. Because gp130 is ubiquitously expressed, this IL-6 trans-signaling substantially increases the spectrum of cells responding to IL-6. In this study, we analyze the role of classical IL-6 signaling and IL-6 trans-signaling in the innate immune response of mice against Listeria monocytogenes infection. We demonstrate that L. monocytogenes infection causes profound systemic IL-6 production and rapid loss of IL-6Rα surface expression on neutrophils, inflammatory monocytes, and different lymphocyte subsets. IL-6–deficient mice or mice treated with neutralizing anti–IL-6 mAb displayed impaired control of L. monocytogenes infection accompanied by alterations in the expression of inflammatory cytokines and chemokines, as well as in the recruitment of inflammatory cells. In contrast, restricted blockade of IL-6 trans-signaling by application or transgenic expression of a soluble gp130 protein did not restrain the control of infection. In summary, our results demonstrate that IL-6Rα surface expression is highly dynamic during the innate response against L. monocytogenes and that the protective IL-6 function is dependent on classical IL-6 signaling via mIL-6Rα.

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“…However, lymphocytes are able to release sIL-6R under specific conditions such as TCR activation [32] and HTLV-transformation [33]. Therefore, the possible contribution of ET lymphocytes to sIL-6R increase was also considered.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Abnormal regulation of soluble and anchored IL-6 receptor in monocytes from patients with essential thrombocythemia

Goette

Lev

Heller

et al. 2010

Experimental Hematology

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Abbreviations used in this paper: ET, essential thrombocythemia; DS-sIL-6R, soluble receptor for IL-6 originated from differential splicing; PC-sIL-6R, soluble receptor for IL-6 originated from proteolytic cleavage; ADAM, a disintegrin and metalloproteinase domain; FCS, fetal calf serum; TAPI, TNF- protease inhibitor; PBMC, peripheral blood mononuclear cells.In a previous study, we found increased plasma sIL-6R levels in patients with essential thrombocythemia (ET) that could promote megakaryocytopoyesis through IL-6 binding and further interaction with the signal transducer gp130. Here we have searched for the cell source of sIL-6R within mononuclear cells in these patients and the underlying abnormalities involved in its overproduction. PATIENTS AND METHODS.Thirty patients with the diagnosis of essential thrombocythemia were studied. sIL-6R levels were measured by ELISA technique in the supernatants of peripheral monocyte and lymphocyte cultures. Expression of membrane anchored IL-6 receptor was determined by flow cytometry. In order to study the mechanism of sIL-6R production, TNF- protease inhibitor (TAPI) was added to specifically block IL-6R shedding. Gene expression of sIL-6R levels were evaluated by RT-PCR. RESULTS.Monocytes were the main source of sIL-6R. Besides, in ET patients, monocyte sIL-6R release was higher than that of controls, p = 0.0014. Lymphocytes enhanced monocyte sIL-6R production by cell-mediated contact in normal controls, but this cooperation could not be seen in patients. Membrane expression of IL-6R was increased after monocyte adhesion in ET. sIL-6R synthesis was up-regulated in most patients while mRNA was normal. CONCLUSION.Our results indicate that ET monocytes are responsible for sIL-6R overproduction within mononuclear cells through synthesis up-regulation. In addition, the lack of cooperation of lymphocytes in monocyte sIL-6R production in ET could be due to a monocyte abnormality. The agonistic effect of sIL-6R on IL-6 action could contribute to the exacerbated megakaryocytic growth in ET.

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Cutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells

Cited by 145 publications

References 29 publications

Loss of CD4+ T Cell IL-6R Expression during Inflammation Underlines a Role for IL-6TransSignaling in the Local Maintenance of Th17 Cells

Loss of CD4+ T Cell IL-6R Expression during Inflammation Underlines a Role for IL-6TransSignaling in the Local Maintenance of Th17 Cells

IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling

Abnormal regulation of soluble and anchored IL-6 receptor in monocytes from patients with essential thrombocythemia

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