The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation

Rose-John, Stefan

doi:10.1002/cpt.782

Cited by 135 publications

(111 citation statements)

References 80 publications

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“…Although IL-6 is largely considered to be a proinflammatory cytokine, it also behaves as an anti-inflammatory agent in specific settings (20,21). Two modalities of IL-6 signaling have been recognized: classic signaling and transsignaling (22). In the present study, we found that a single dose of rCT-1 enhances IL-6 secretion ( Fig.…”

Section: Interplay Between Ct-1 and Il-6 In The Modulation Of Inflammsupporting

confidence: 56%

Cardiotrophin‐1 is an anti‐inflammatory cytokine and promotes IL‐4–induced M2 macrophage polarization

et al. 2019

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Macrophages play a central role in tissue remodeling, repair, and resolution of inflammation. Macrophage polarization to Ml or M2 activation status may determine the progression or resolution of the inflammatory response. We have previously reported that cardiotrophin‐1 (CT‐1) displays both cytoprotective and metabolic activities. The role of CT‐1 in inflammation remains poorly understood. Here, we employed recombinant CT‐1 (rCT‐1) and used CT‐1–null mice and myeloid‐specif ic CT‐1 transgenic mice to investigate whether CT‐1 might play a role in the modulation of the inflammatory response. We observed that CT‐1 deficiency was associated with enhanced release of inflammatory mediators and with stronger activation of NF‐κB in response to LPS, whereas the inflammatory response was attenuated in CT‐1 transgenic mice or by administering rCT‐1 to wild‐type animals prior to LPS challenge. We found that CT‐1 promoted IL‐6 expression only by nonhematopoietic cells, whereas LPS up‐regulated IL‐6 expression in both hematopoietic and nonhematopoietic cells. Notably, rCT‐1 inhibited LPS‐mediated soluble IL‐6R induction. Using IL‐6−/− mice, we showed that rCT‐1 inhibited LPS‐induced TNF‐α and IFN‐γ response in an IL‐6–independent manner. Importantly, we demonstrated that CT‐1 primes macrophages for IL‐4–dependent M2 polarization by inducing IL‐4 receptor expression. Mechanistic analyses showed that the signal transducer and activator of transcription 3–suppressor of cytokine signaling 3 axis mediates this effect. Our findings support the notion that CT‐1 is a critical regulator of inflammation and suggest that rCT‐1 could be a molecule with potential therapeutic application in inflammatory conditions.—Carneros, D., Santamaría, E. M., Larequi, E., Vélez‐Ortiz, J. M., Reboredo, M., Mancheño, U., Perugorria, M. J., Navas, P., Romero‐Gómez, M., Prieto, J., Hervás‐Stubbs, S., Bustos, M. Cardiotrophin‐1 is an anti‐inflammatory cytokine and promotes IL‐4–induced M2 macrophage polarization. FASEB J. 33, 7578–7587 (2019). http://www.fasebj.org

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Section: Interplay Between Ct-1 and Il-6 In The Modulation Of Inflammsupporting

confidence: 56%

Cardiotrophin‐1 is an anti‐inflammatory cytokine and promotes IL‐4–induced M2 macrophage polarization

et al. 2019

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“…Besides small‐molecule drugs and antibodies, shed substrate ectodomains may be employed as decoy receptors. For example, recombinant soluble gp130, corresponding to the shed gp130 ectodomain, is used to block excessive IL‐6 signaling in inflammatory conditions and is currently being tested in a phase II clinical trial (reviewed in Rose‐John, ). Another important example of a shedding‐related condition is Alzheimer's disease, where pathogenic amyloid‐β peptide results from shedding of APP by BACE1 followed by γ‐secretase‐mediated intramembrane proteolysis.…”

Section: Disease Association and Shedding‐based Drugsmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

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“…IL-6R is mainly found on hepatocytes and immune cells, thereby restricting the number of cells targeted by IL-6 classic signaling. IL-6 classic signaling induces the acute-phase response and is considered to have homeostatic and anti-inflammatory effects (7). Because gp130 is ubiquitously expressed, trans-signaling via the sIL-6R can activate virtually all cells of the body.…”

mentioning

confidence: 99%

“…Because gp130 is ubiquitously expressed, trans-signaling via the sIL-6R can activate virtually all cells of the body. IL-6 trans-signaling mainly regulates pro-inflammatory reactions (7). A soluble form of gp130 (sgp130) has been shown to specifically inhibit IL-6 trans-signaling, whereas IL-6 classic signaling is largely unaffected (3,8).…”

mentioning

confidence: 99%

The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling

Baran

Hansen

Waetzig

et al. 2018

Journal of Biological Chemistry

158

132

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Interleukin (IL-)6 is the major pro-inflammatory cytokine within the IL-6 family. IL-6 signals via glycoprotein 130 (gp130) and the membrane-bound or soluble IL-6 receptor (IL-6R), referred to as classic or trans-signaling, respectively. Whereas inflammation triggers IL-6 expression, eventually rising to nanogram/ml serum levels, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130) are constitutively present in the upper nanogram/ml range. Calculations based on intermolecular affinities have suggested that systemic IL-6 is immediately trapped in IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, indicating that sIL-6R and sgp130 constitute a buffer system that increases the serum half-life of IL-6 or restricts systemic IL-6 signaling. However, this scenario has not been experimentally validated. Here, we quantified IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes over a wide concentration range. The amounts of IL-6 used in this study reflect concentrations found during active inflammatory events. Our results indicated that most IL-6 is free and not complexed with sIL-6R or sgp130, indicating that the level of endogenous sgp130 in the bloodstream is not sufficient to block IL-6 trans-signaling via sIL-6R. Importantly, addition of the single-domain antibody VHH6, which specifically stabilizes IL-6·sIL-6R complexes but did not bind to IL-6 or sIL-6R alone, drove free IL-6 into IL-6·sIL-6R complexes and boosted trans-signaling but not classic signaling, demonstrating that endogenous sIL-6R has at least the potential to form complexes with IL-6. Our findings indicate that even though high concentrations of sIL-6R and sgp130 are present in human serum, the relative ratio of free IL-6 to IL-6·sIL-6R allows for simultaneous classic and trans-signaling.

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The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation

Cited by 135 publications

References 80 publications

Cardiotrophin‐1 is an anti‐inflammatory cytokine and promotes IL‐4–induced M2 macrophage polarization

Cardiotrophin‐1 is an anti‐inflammatory cytokine and promotes IL‐4–induced M2 macrophage polarization

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling

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