Letter to Editor
Peripheral IL-6 signaling: a promising therapeutic target for depression? Chun Yang & Kenji Hashimoto†
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by CDL-UC San Diego on 06/12/15 For personal use only.
Chiba University Center for Forensic Mental Health, Division of Clinical Neuroscience, Chiba, Japan
Accumulating evidence suggests that up-regulation of pro-inflammatory cytokines, including IL-6, play a role in the pathogenesis of depression. Furthermore, IL-6 is an important cytokine which is involved in the pathogenesis and treatment of depression. A recent review concluded that novel investigational drugs targeting IL-6 signaling could be beneficial for the treatment of depression [1]. We totally agree with this conclusion. In this letter, we would like to propose that peripheral IL-6 would be a promising target to treat depressive symptoms. Peripheral IL-6 is secreted from macrophages and monocytes to stimulate differentiation and proliferation of B cells. A recent paper demonstrated elevated serum IL-6 levels in patients with major depression but has presented mixed results (no change or decrease) with IL-6 levels in cerebrospinal fluid (CSF) [2]. Furthermore, a recent meta-analysis concluded that blood levels of IL-6 in patients with suicidality were significantly higher than those of patients without suicidality and healthy control subjects, suggesting that peripheral IL-6 may be associated with suicidal ideation, a core symptom of depression [3]. Very recently, we also reported that serum IL-6 may be a predictable biomarker for ketamine’s antidepressant effect in patients with treatment-resistant major depression [4]. Moreover, we found that alterations in peripheral IL-6, but not in the brain, may contribute to resilience versus susceptibility to inescapable stress in rat learned helplessness (LH) model [5]. Thus, it is unlikely that brain IL-6 may be involved in the pathogenesis of depression. At present, commercially available IL-6 antagonists such as tocilizumab (ACTEMRAÒ) have been widely used to treat patients with rheumatoid arthritis which was characterized by excessive expressed pro-inflammatory cytokines in peripheral tissues. Collectively, these results suggest that the novel drugs targeting peripheral IL-6 could show beneficial effects for depression. Future detailed studies on peripheral IL-6 signaling in the treatment of depression are needed.
Declaration of interest The authors are supported by a Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K Hashimoto, #24116006). C Yang was supported by the Uehara Memorial Foundation (Tokyo, Japan). K Hashimoto has also served as a scientific consultant to Astellas, Dainippon-Sumitomo and Taisho, and he has also received research support from Abbvie, Dainippon-Sumitomo, Mochida, Otsuka, and Taisho. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
10.1517/13543784.2015.1055669 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
1
C. Yang & K. Hashimoto
Bibliography Fonseka TM, McIntyre RS, Soczynska JK, et al.Novel investigational drugs targeting IL-6 signaling for the treatment of depression. Expert Opin Investig Drugs 2015;24(4):459-75
2.
Young JJ, Bruno D, Pomara N. A review of the relationship between proinflammatory cytokines and major depressive disorder. J Affect Disord 2014;169:15-20
3.
Black C, Miller BJ. Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by CDL-UC San Diego on 06/12/15 For personal use only.
1.
2
patients. Biol Psychiatry 2015;doi: 10.1016/j. biopsych.2014.10.014. [Epub ahead of print] 4.
Yang JJ, Wang N, Yang C, et al. Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry 2015;77(3):e19-20
5.
Yang C, Shirayama Y, Zhang JC, et al. Peripheral interleukin-6 promotes resilience versus susceptibility to
Expert Opin. Investig. Drugs (2015) 24(7)
inescapable electric stress. Acta Neuropsychiatr 2015; doi: 10.1017/neu.2015.36
Affiliation
Chun Yang & Kenji Hashimoto† † Author for correspondence Chiba University Center for Forensic Mental Health, Division of Clinical Neuroscience, Chiba 260-8670, Japan Tel: +81 43 226 2517; Fax: +81 43 226 2561; E-mail: [email protected]
Peripheral IL-6 signaling: a promising therapeutic target for depression? Chun Yang & Kenji Hashimoto†
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by CDL-UC San Diego on 06/12/15 For personal use only.
Chiba University Center for Forensic Mental Health, Division of Clinical Neuroscience, Chiba, Japan
Accumulating evidence suggests that up-regulation of pro-inflammatory cytokines, including IL-6, play a role in the pathogenesis of depression. Furthermore, IL-6 is an important cytokine which is involved in the pathogenesis and treatment of depression. A recent review concluded that novel investigational drugs targeting IL-6 signaling could be beneficial for the treatment of depression [1]. We totally agree with this conclusion. In this letter, we would like to propose that peripheral IL-6 would be a promising target to treat depressive symptoms. Peripheral IL-6 is secreted from macrophages and monocytes to stimulate differentiation and proliferation of B cells. A recent paper demonstrated elevated serum IL-6 levels in patients with major depression but has presented mixed results (no change or decrease) with IL-6 levels in cerebrospinal fluid (CSF) [2]. Furthermore, a recent meta-analysis concluded that blood levels of IL-6 in patients with suicidality were significantly higher than those of patients without suicidality and healthy control subjects, suggesting that peripheral IL-6 may be associated with suicidal ideation, a core symptom of depression [3]. Very recently, we also reported that serum IL-6 may be a predictable biomarker for ketamine’s antidepressant effect in patients with treatment-resistant major depression [4]. Moreover, we found that alterations in peripheral IL-6, but not in the brain, may contribute to resilience versus susceptibility to inescapable stress in rat learned helplessness (LH) model [5]. Thus, it is unlikely that brain IL-6 may be involved in the pathogenesis of depression. At present, commercially available IL-6 antagonists such as tocilizumab (ACTEMRAÒ) have been widely used to treat patients with rheumatoid arthritis which was characterized by excessive expressed pro-inflammatory cytokines in peripheral tissues. Collectively, these results suggest that the novel drugs targeting peripheral IL-6 could show beneficial effects for depression. Future detailed studies on peripheral IL-6 signaling in the treatment of depression are needed.
Declaration of interest The authors are supported by a Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to K Hashimoto, #24116006). C Yang was supported by the Uehara Memorial Foundation (Tokyo, Japan). K Hashimoto has also served as a scientific consultant to Astellas, Dainippon-Sumitomo and Taisho, and he has also received research support from Abbvie, Dainippon-Sumitomo, Mochida, Otsuka, and Taisho. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
10.1517/13543784.2015.1055669 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
1
C. Yang & K. Hashimoto
Bibliography Fonseka TM, McIntyre RS, Soczynska JK, et al.Novel investigational drugs targeting IL-6 signaling for the treatment of depression. Expert Opin Investig Drugs 2015;24(4):459-75
2.
Young JJ, Bruno D, Pomara N. A review of the relationship between proinflammatory cytokines and major depressive disorder. J Affect Disord 2014;169:15-20
3.
Black C, Miller BJ. Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal
Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by CDL-UC San Diego on 06/12/15 For personal use only.
1.
2
patients. Biol Psychiatry 2015;doi: 10.1016/j. biopsych.2014.10.014. [Epub ahead of print] 4.
Yang JJ, Wang N, Yang C, et al. Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry 2015;77(3):e19-20
5.
Yang C, Shirayama Y, Zhang JC, et al. Peripheral interleukin-6 promotes resilience versus susceptibility to
Expert Opin. Investig. Drugs (2015) 24(7)
inescapable electric stress. Acta Neuropsychiatr 2015; doi: 10.1017/neu.2015.36
Affiliation
Chun Yang & Kenji Hashimoto† † Author for correspondence Chiba University Center for Forensic Mental Health, Division of Clinical Neuroscience, Chiba 260-8670, Japan Tel: +81 43 226 2517; Fax: +81 43 226 2561; E-mail: [email protected]
