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Tadamitsu Kishimoto - One of the best experts on this subject based on the ideXlab platform.
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a case of behcet s disease treated with a humanized anti Interleukin 6 Receptor antibody tocilizumab
Modern Rheumatology, 2012Co-Authors: Toru Hirano, Nobuyuki Ohguro, Satoshi Hohki, Keisuke Hagihara, Yoshihito Shima, Masashi Narazaki, Atsushi Ogata, Kazuyuki Yoshizaki, Atsushi Kumanogoh, Tadamitsu KishimotoAbstract:A 47-year-old female patient with Behcet’s disease had been treated with colchicine, prednisolone, cyclosporine A, and infliximab. Because she relapsed, however, treatment with tocilizumab, a humanized anti-Interleukin 6 Receptor antibody, was started. This treatment suppressed the patient’s clinical manifestations, including ocular attacks, for 1 year and improved her visual acuity. This experience indicates that tocilizumab may constitute a therapeutic option for refractory Behcet’s disease.
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A case of Behçet’s disease treated with a humanized anti-Interleukin-6 Receptor antibody, tocilizumab
Modern Rheumatology, 2011Co-Authors: Toru Hirano, Nobuyuki Ohguro, Satoshi Hohki, Keisuke Hagihara, Yoshihito Shima, Masashi Narazaki, Atsushi Ogata, Kazuyuki Yoshizaki, Atsushi Kumanogoh, Tadamitsu KishimotoAbstract:A 47-year-old female patient with Behcet’s disease had been treated with colchicine, prednisolone, cyclosporine A, and infliximab. Because she relapsed, however, treatment with tocilizumab, a humanized anti-Interleukin 6 Receptor antibody, was started. This treatment suppressed the patient’s clinical manifestations, including ocular attacks, for 1 year and improved her visual acuity. This experience indicates that tocilizumab may constitute a therapeutic option for refractory Behcet’s disease.
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Pharmacotherapy Options in Rheumatoid Arthritis: Focus on Tocilizumab, a Recombinant Humanized Anti-Interleukin-6 Receptor Antibody
Clinical Medicine and Therapeutics, 2009Co-Authors: Yoshiyuki Ohsugi, Tadamitsu KishimotoAbstract:Evidence has accumulated indicating that proinflammatory cytokines play critical roles in the pathogenesis of RA. Recent clinical studies demonstrate that blockade of IL-6 signaling with tocilizumab, a recombinant humanized anti-Interleukin-6 Receptor antibody, is a new therapeutic option for the treatment of patients with RA refractory to conventional DMARD therapy and anti-TNF-α therapy. This paper discusses possible mechanisms of action, reviews the results of clinical trials, and discusses the place of tocilizumab in RA treatment.
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Differential shedding of the two subunits of the Interleukin‐6 Receptor
FEBS Letters, 1993Co-Authors: Jürgen Müllberg, Elke Dittrich, Lutz Graeve, Claudia Gerhartz, Kiyoshi Yasukawa, Tetsuya Taga, Tadamitsu Kishimoto, Peter C. Heinrich, Stefan Rose-johnAbstract:cDNAs coding for the two Receptor subunits of the Interleukin-6 Receptor have been stably expressed in Madine Darby canine kidney (MDCK) cells. The fate of the IL-6 binding protein (IL-6R) and of the signal transducing protein gp130 was studied independently. Both proteins were proteolytically cleaved from cells metabolically labeled with [35S]methionine/cysteine leading to the release of soluble Receptor proteins of 55 kDa and 100 kDa, respectively. In contrast to the shedding of the IL-6R gp 130 was inefficiently released from the cells and the process was not significantly stimulated by the phorbolester PMA. In addition we show that the soluble forms of the IL-6R and gp 130 released by transfected cells can form a ternary complexe with Interleukin-6 indicating that such complexes also may occur in vivo. gp 130; Interleukin-6; Interleukin-6-Receptor; Protein kinase C; Shedding
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Soluble Interleukin‐6 Receptor Is Released from Receptor‐bearing Cell Lines in vitro
Japanese Journal of Cancer Research, 1992Co-Authors: Toshiharu Nakajima, Kiyoshi Yasukawa, Tadamitsu Kishimoto, Toshio Hirano, Shinji Yamamoto, Ming Cheng, Tohru Tokunaga, Mitsuo HondaAbstract:Soluble Interleukin-6 Receptor (sIL-6R) was found to be spontaneously released from human myeloma cell line U266 cells into culture supernatant, and was quantitatively measured with a fluorescence sandwich enzyme-linked immunosorbent assay employing antibodies specific to IL-6R. The supernatant IL-6R was generated only from IL-6R-positive cell lines; myeloma cell lines RPMI8226 and RPMI1788, and myelomonocytic cell lines U937, THP-1, and HL-60. In contrast, it was not released from the IL-6R-negative cells; T cell line MoIt-4 and Burkitt lympboma cell line Raji. SDS-PAGE analysis of the soluble IL-6R from U266 cells suggested a molecular weight of approximately 50-55 kDa, 25–30 kDa smaller than the mature cell surface Receptor. These results suggest that the generation of soluble IL-6R may be a maker of myeloma cells and myelomonocytic cells.
Christoph Garbers - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic blockade of the Interleukin-6 Receptor (IL-6R) allows sIL-6R generation by proteolytic cleavage
Cytokine, 2018Co-Authors: Niklas Prenissl, Stefan Rose-john, Juliane Lokau, Johannes Haybaeck, Christoph GarbersAbstract:Abstract Blockade of the Interleukin-6 Receptor (IL-6R) is a successful therapeutic strategy in various inflammatory diseases. IL-6 can signal via membrane-bound (classic signaling) and soluble forms (sIL-6R, trans-signaling) of the IL-6R. Trans-signaling is causative for the pro-inflammatory properties of IL-6, and the selective inhibition of this pathway holds the promise to cause less side effects than the global blockade of IL-6 signaling. We have recently shown that the majority of sIL-6R in humans is generated by proteolytic cleavage of the membrane-bound IL-6R, but whether this process is influenced by therapeutic blockade of the IL-6R is unknown. In this study, we show that the monoclonal antibody tocilizumab and a single chain antibody directed against the IL-6R efficiently block IL-6 signaling, but do not prevent the proteolytic generation of sIL-6R.
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ID: 196: Proteolysis of the human Interleukin-6 Receptor in vivo
Cytokine, 2015Co-Authors: Christoph Garbers, Steffen Riethmüller, Prasath Somasundaram, Johanna C. Ehlers, Tomas Koudelka, Chien-wen Hung, Andreas Tholey, Stefan Rose-johnAbstract:Interleukin-6 (IL-6) has been linked to numerous inflammatory diseases and is therefore an attractive therapeutic target in the clinic. Soluble and membrane-bound forms of the Interleukin-6 Receptor (IL-6R) are responsible for its pro- and anti-inflammatory properties via the membrane-bound β -Receptor gp130. Formation of the signaling complex results in activation of the JAK/STAT signaling pathway. In addition, soluble forms of the IL-6R (sIL-6R) have been identified in several body fluids. Interestingly, a coding nonsynonymous single nucleotide polymorphism (SNP) within the IL-6R (rs2228145, Asp358Ala) results in a 2-fold increase in soluble IL-6R (sIL-6R) serum levels and a reduced risk for coronary heart disease. In vitro data show that the sIL-6R is generated either via limited proteolysis of the membrane-bound precursor or via alternative splicing of the IL-6R mRNA, and the latter has been shown to occur also in vivo . In order to identify and analyze sIL-6R that was generated by proteolysis we combined a “bottom-up” proteomics approach with LC-MS. We could determine the cleavage site used in vitro and in vivo , identify novel glycan motifs, and show for the first time that proteolysis contributes to sIL-6R serum levels in humans. Further analysis of N- and O-linked glycosylation revealed different functions in terms of signaling and proteolysis. Mutation of the identified cleavage site resulted in an IL-6R that was resistant towards shedding by ADAM10 and ADAM17. In summary, our data show that limited proteolysis contributes to sIL-6R serum levels in humans, and that glycosylation is an important regulatory modification of the IL-6R.
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the Interleukin 6 Receptor asp358ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by adam proteases
Biochimica et Biophysica Acta, 2014Co-Authors: Simon Arnett Jones, Stefan Rosejohn, Christoph Garbers, Juliane Lokau, Niloufar Monhasery, Samadhi Apariciosiegmund, Paul Baran, Mari Ann Nowell, Jurgen SchellerAbstract:The pleiotropic activities of Interleukin (IL-)6 are controlled by membrane-bound and soluble forms of the IL-6 Receptor (IL-6R) in processes called classic and trans-signaling, respectively. The coding single nucleotide polymorphism (SNP) rs2228145 of the Interleukin 6 Receptor (IL-6R Asp358Ala variant) is associated with a 2-fold increase in soluble IL-6R (sIL-6R) serum levels resulting in reduced IL-6-induced C-reactive protein (CRP) production and a reduced risk for coronary heart disease. It was suggested that the increased sIL-6R level leads to decreased IL-6 classic or increased IL-6 trans-signaling. Irrespective of the functional outcome of increased sIL-6R serum level, it is still under debate, whether the increased sIL-6R serum levels emerged from differential splicing or ectodomain shedding. Here we show that increased proteolytic ectodomain shedding mediated by the A Disintegrin and metalloproteinase domain (ADAM) proteases ADAM10 and ADAM17 caused increased sIL-6R serum level in vitro as well as in healthy volunteers homozygous for the IL-6R Asp358Ala allele. Differential splicing of the IL-6R appears to have only a minor effect on sIL-6R level. Increased ectodomain shedding resulted in reduced cell-surface expression of the IL-6R Asp358Ala variant compared to the common IL-6R variant. In conclusion, increased IL-6R ectodomain shedding is a mechanistic explanation for the increased serum IL-6R levels found in persons homozygous for the rs2228145 IL-6R Asp358Ala variant.
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the soluble Interleukin 6 Receptor generation and role in inflammation and cancer
European Journal of Cell Biology, 2011Co-Authors: Athena Chalaris, Stefan Rosejohn, Christoph Garbers, Bjorn Rabe, Jurgen SchellerAbstract:Soluble cytokine Receptors are frequently found in human serum, most of them possessing antagonistic properties. The Interleukin 6 Receptor (IL-6R) is found as a transmembrane protein on hepatocytes and subsets of leukocytes, but soluble isoforms of the IL-6R (sIL-6R) are generated by alternative splicing or by limited proteolysis of the ADisintegrin And Metalloproteinases (ADAM) gene family members ADAM10 and ADAM17. Importantly, the sIL-6R in complex with its ligand Interleukin 6 (IL-6) has agonistic functions and requires cells expressing the signal transducing s-Receptor gp130 but not the membrane-bound IL-6R. We have called this process IL-6 trans-signaling. Naturally occurring isoforms of soluble gp130 (sgp130), which are generated by alternative splicing, are natural inhibitors of IL-6 trans-signaling, leaving IL-6 classic signaling via the membrane-bound IL-6R unaffected. We used recombinant sgp130Fc protein and recently generated transgenic mice expressing high levels of sgp130Fc to discriminate between classic and trans-signaling in vivo, and demonstrated that IL-6 trans-signaling is critically involved in generation and maintenance of several inflammatory and autoimmune diseases including chronic inflammatory bowel disease, rheumatoid arthritis, peritonitis and asthma, as well as inflammation-induced colon cancer.
Annamaria Corsi - One of the best experts on this subject based on the ideXlab platform.
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a common variant of the Interleukin 6 Receptor il 6r gene increases il 6r and il 6 levels without other inflammatory effects
Genes and Immunity, 2007Co-Authors: Sajjad Rafiq, Timothy M. Frayling, Anna Murray, Alison J. Hurst, Kara Stevens, Michael N. Weedon, William Henley, Luigi Ferrucci, Stefania Bandinelli, Annamaria CorsiAbstract:Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 Receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with Interleukin 6 Receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r(2)=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13-140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35-71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 x 10(-62). The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 x 10(-4)). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.
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A common variant of the Interleukin 6 Receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects
Genes and Immunity, 2007Co-Authors: Sajjad Rafiq, Timothy M. Frayling, Anna Murray, Alison J. Hurst, Kara Stevens, Michael N. Weedon, William Henley, Luigi Ferrucci, Stefania Bandinelli, Annamaria CorsiAbstract:A common variant of the Interleukin 6 Receptor ( IL-6r ) gene increases IL-6r and IL-6 levels, without other inflammatory effects
Stefan Rose-john - One of the best experts on this subject based on the ideXlab platform.
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Shedding of Interleukin-6 Receptor and tumor necrosis factor α
FEBS Journal, 2020Co-Authors: Katja Althoff, Stefan Rose-john, Pranitha Reddy, Nicole Voltz, Jürgen MüllbergAbstract:A functionally and structurally diverse group of transmembrane proteins including transmembrane forms of mediators or Receptors can be proteolytically cleaved to form soluble growth factors or Receptors. Recently, the proteolytic activity responsible for pro-tumor necrosis factor α (proTNFα) processing has been identified and named TACE (TNFα converting enzyme). In experiments with TACE deficient (TACE-/-) fibroblasts we found that 4β-phorbol 12-myristate 13-acetate (PMA)-induced shedding of the Interleukin-6 Receptor (IL-6R) is strongly reduced. A basal hydroxamate sensitive release of IL-6R, however, could still be detected. This result demonstrates that TACE plays a role in IL-6R processing and that additional metalloproteases might be involved. PMA-induced shedding of IL-6R in TACE deficient mouse fibroblasts could be restored by stable transfection of a TACE cDNA. To characterize differences between shedding of IL-6R and proTNFα we generated chimeric IL-6R and proTNFα proteins wherein the endogenous cleavage sites (CS) had been replaced by the corresponding region of proTNFα and IL-6R, respectively. Interestingly, proTNFα chimeric proteins showed only minimal shedding. In contrast, IL-6R chimeras containing the proTNFα CS were shed spontaneously, processing was not further induced by PMA. Thus, the cleavage pattern transferred by the introduction of the proTNFα CS is similar to that of proTNFα itself. We conclude that the amino-acid sequence at the proteolytic CS contributes to the cleavage characteristics of a protein. However, this information alone is not sufficient to transfer cleavability as seen with proTNFα chimeras containing the IL-6R CS and which were resistant to shedding.
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Therapeutic blockade of the Interleukin-6 Receptor (IL-6R) allows sIL-6R generation by proteolytic cleavage
Cytokine, 2018Co-Authors: Niklas Prenissl, Stefan Rose-john, Juliane Lokau, Johannes Haybaeck, Christoph GarbersAbstract:Abstract Blockade of the Interleukin-6 Receptor (IL-6R) is a successful therapeutic strategy in various inflammatory diseases. IL-6 can signal via membrane-bound (classic signaling) and soluble forms (sIL-6R, trans-signaling) of the IL-6R. Trans-signaling is causative for the pro-inflammatory properties of IL-6, and the selective inhibition of this pathway holds the promise to cause less side effects than the global blockade of IL-6 signaling. We have recently shown that the majority of sIL-6R in humans is generated by proteolytic cleavage of the membrane-bound IL-6R, but whether this process is influenced by therapeutic blockade of the IL-6R is unknown. In this study, we show that the monoclonal antibody tocilizumab and a single chain antibody directed against the IL-6R efficiently block IL-6 signaling, but do not prevent the proteolytic generation of sIL-6R.
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ID: 196: Proteolysis of the human Interleukin-6 Receptor in vivo
Cytokine, 2015Co-Authors: Christoph Garbers, Steffen Riethmüller, Prasath Somasundaram, Johanna C. Ehlers, Tomas Koudelka, Chien-wen Hung, Andreas Tholey, Stefan Rose-johnAbstract:Interleukin-6 (IL-6) has been linked to numerous inflammatory diseases and is therefore an attractive therapeutic target in the clinic. Soluble and membrane-bound forms of the Interleukin-6 Receptor (IL-6R) are responsible for its pro- and anti-inflammatory properties via the membrane-bound β -Receptor gp130. Formation of the signaling complex results in activation of the JAK/STAT signaling pathway. In addition, soluble forms of the IL-6R (sIL-6R) have been identified in several body fluids. Interestingly, a coding nonsynonymous single nucleotide polymorphism (SNP) within the IL-6R (rs2228145, Asp358Ala) results in a 2-fold increase in soluble IL-6R (sIL-6R) serum levels and a reduced risk for coronary heart disease. In vitro data show that the sIL-6R is generated either via limited proteolysis of the membrane-bound precursor or via alternative splicing of the IL-6R mRNA, and the latter has been shown to occur also in vivo . In order to identify and analyze sIL-6R that was generated by proteolysis we combined a “bottom-up” proteomics approach with LC-MS. We could determine the cleavage site used in vitro and in vivo , identify novel glycan motifs, and show for the first time that proteolysis contributes to sIL-6R serum levels in humans. Further analysis of N- and O-linked glycosylation revealed different functions in terms of signaling and proteolysis. Mutation of the identified cleavage site resulted in an IL-6R that was resistant towards shedding by ADAM10 and ADAM17. In summary, our data show that limited proteolysis contributes to sIL-6R serum levels in humans, and that glycosylation is an important regulatory modification of the IL-6R.
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The soluble Interleukin-6 Receptor and related proteins
Best Practice & Research Clinical Endocrinology & Metabolism, 2015Co-Authors: Stefan Rose-johnAbstract:Interleukin-6 is a cytokine involved in the regulation of the immune system and the central nervous system. Interleukin-6 binds to an Interleukin-6 Receptor, and then associates with a dimer of the ubiquitously expressed gp130 Receptor subunit, which initiates intracellular signaling. The Interleukin-6 Receptor is found in a soluble form, which is generated by proteolytic cleavage and also to a minor extent by translation from an alternatively spliced mRNA. The complex of Interleukin-6 bound to the Interleukin-6 Receptor can stimulate cells, which only express gp130. Such cells are not responsive to Interleukin-6 alone. We have for the first time identified the molecular basis of pro-and anti-inflammatory properties of Interleukin-6 and we have defined the generation of the soluble IL-6R as a crucial point in the regulation between these two properties. Furthermore, we have deduced a therapeutic principle, which enables us to exclusively block the pro-inflammatory activities of this important cytokine.
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Direct Determination of the Interleukin-6 Binding Epitope of the Interleukin-6 Receptor by NMR Spectroscopy
Journal of Biological Chemistry, 2003Co-Authors: Andreas Schwantner, Stefan Rose-john, Andrew J. Dingley, Suat Özbek, Joachim GrötzingerAbstract:Abstract All cytokines belonging to the Interleukin-6 (IL-6)-type family of cytokines utilize Receptors that have a modular build of several immunoglobulin-like and fibronectin type III-like domains. Characteristic of these Receptors is a cytokine Receptor homology region consisting of two such fibronectin domains defined by a set of four conserved cysteines and a tryptophan-serine-X-tryptophan-serine sequence motif. On target cells, Interleukin-6 first binds to its specific Receptor and subsequently to a homodimer of the signal transducer protein gp130. The Interleukin-6 Receptor consists of three extracellular domains. The N-terminal immunoglobulin-like domain is not involved in ligand binding, whereas the third membrane proximal fibronectin-like domain accounts for more than 90% of the binding energy to IL-6. Here, the key residues of this fibronectin-like domain involved in the interaction with IL-6 are described. Chemical shift mapping data with 15N-labeled IL-6R-D3 and unlabeled IL-6 coupled with recent structural data clearly reveal the epitope within the IL-6R-D3 responsible for mediating the high affinity interaction with its cognate cytokine.
Masatoshi Takeda - One of the best experts on this subject based on the ideXlab platform.
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Serum level of soluble Interleukin 6 Receptor is a useful biomarker for identification of treatment‐resistant major depressive disorder
2020Co-Authors: Katsuhiko Yamasaki, Tomonori Hasegawa, Masatoshi TakedaAbstract:AIM: A substantial proportion of major depressive disorder patients are treatment-resistant to antidepressant therapy, who require augmentation drugs, or other treatments including electroconvulsive therapy or transcranial magnetic stimulation. Identifying treatment-resistant major depressive disorder patients before the actual administration of antidepressant is, however, often difficult. Accordingly, the serum biomarker to identify treatment-resistant patients will be helpful in clinical settings. This study aims to clarify the appropriate biomarkers for identification of treatment-resistant major depressive disorder. METHOD: Given that immune-inflammatory processes are involved in the pathogenesis of major depressive disorder, it is possible that certain cytokine-related molecules could serve as clinically useful biomarkers of treatment-resistant major depressive disorder patients. In this study, we measured serum levels of tumor necrosis factor-alpha, Interleukin 6, and soluble Interleukin 6 Receptor after major depressive disorder patients underwent antidepressant therapy. RESULTS: The serum level of soluble Interleukin 6 Receptor, but not Interleukin 6 or tumor necrosis factor-alpha, was significantly higher in treatment-resistant major depressive disorder patients than in remitted patients, suggesting that serum soluble Interleukin 6 Receptor could be a good biomarker of treatment-resistant major depressive disorder. Receiver operating characteristic analysis confirmed that serum soluble Interleukin-6 Receptor level measurement was useful for identification of treatment-resistant major depressive disorder patients. Multiple regression analysis using the serum levels of the aforementioned cytokines as explanatory variables and the Quick Inventory of Depressive Symptomatology-Self Report score (QIDS-SR16 ) as a target variable showed that only serum soluble Interleukin-6 Receptor level could explain the severity of major depressive disorder. CONCLUSION: Based on these results, we recommend measurement of serum soluble Interleukin-6 Receptor level to discriminate treatment-resistant major depressive disorder patients. High serum soluble Interleukin-6 Receptor level is associated with the pathogenesis of treatment-resistant major depressive disorder, suggesting the involvement of the Interleukin 6 trans-signaling system in onset of treatment-resistant major depressive disorder.
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Serum level of soluble Interleukin 6 Receptor is a useful biomarker for identification of treatment-resistant major depressive disorder.
Neuropsychopharmacology reports, 2020Co-Authors: Katsuhiko Yamasaki, Tomonori Hasegawa, Masatoshi TakedaAbstract:A substantial proportion of major depressive disorder patients are treatment-resistant to antidepressant therapy, who require augmentation drugs, or other treatments including electroconvulsive therapy or transcranial magnetic stimulation. Identifying treatment-resistant major depressive disorder patients before the actual administration of antidepressant is, however, often difficult. Accordingly, the serum biomarker to identify treatment-resistant patients will be helpful in clinical settings. This study aims to clarify the appropriate biomarkers for identification of treatment-resistant major depressive disorder. Given that immune-inflammatory processes are involved in the pathogenesis of major depressive disorder, it is possible that certain cytokine-related molecules could serve as clinically useful biomarkers of treatment-resistant major depressive disorder patients. In this study, we measured serum levels of tumor necrosis factor-α, Interleukin 6, and soluble Interleukin 6 Receptor after major depressive disorder patients underwent antidepressant therapy. The serum level of soluble Interleukin 6 Receptor, but not Interleukin 6 or tumor necrosis factor-α, was significantly higher in treatment-resistant major depressive disorder patients than in remitted patients, suggesting that serum soluble Interleukin 6 Receptor could be a good biomarker of treatment-resistant major depressive disorder. Receiver operating characteristic analysis confirmed that serum soluble Interleukin-6 Receptor level measurement was useful for identification of treatment-resistant major depressive disorder patients. Multiple regression analysis using the serum levels of the aforementioned cytokines as explanatory variables and the Quick Inventory of Depressive Symptomatology-Self Report score (QIDS-SR16 ) as a target variable showed that only serum soluble Interleukin-6 Receptor level could explain the severity of major depressive disorder. Based on these results, we recommend measurement of serum soluble Interleukin-6 Receptor level to discriminate treatment-resistant major depressive disorder patients. High serum soluble Interleukin-6 Receptor level is associated with the pathogenesis of treatment-resistant major depressive disorder, suggesting the involvement of the Interleukin 6 trans-signaling system in onset of treatment-resistant major depressive disorder. © 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology.