Katsuhiko Yamasaki

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.

Two species of the cDNAs encoding murine IL-6-R (one is abnormal and the other authentic) have been cloned from a plasmacytoma cell line, P3U1, and BALB/c mouse spleen cDNA libraries. In the cDNA encoding the abnormal IL-6-R, the region corresponding to an intracytoplasmic domain was replaced with a part of the long terminal repeat of the intracisternal A particle gene (IAP-LTR). The authentic IL-6-R consists of 460 amino acids with the domain of the Ig superfamily. The overall homology between murine and human IL-6-R was 69 and 54% at DNA and protein levels, respectively. The extracellular domain after the Ig-like domain of murine IL-6-R was found to have an homology with those of murine erythropoietin R, human IL-2-R beta chain, murine IL-4-R, and human granulocyte-macrophage CSF-R, as in the case of human IL-6-R, and these receptors have been classified as members of the IL receptor family. In P3U1 cells, the expression of the mRNA encoding abnormal IL-6-R was much higher than that of the mRNA encoding authentic IL-6-R. An IL-6-dependent human T cell line, KT-3, which did not respond to murine IL-6, acquired the responsiveness to murine IL-6 when transfected with the cDNA encoding abnormal IL-6-R, indicating that abnormal IL-6-R lacking a normal cytoplasmic domain can function. Since IL-6 functions as a potent growth factor for murine plasmacytomas, over-expression of abnormal IL-6-R may function as a positive selection element for the development of certain plasmacytomas.

Interleukin 6 (IL-6)/B cell stimulatory factor 2 is a multifunctional cytokine produced by both lymphoid and nonlymphoid cells. IL-6 regulates immune response, acute phase reaction, and hematopoiesis. It was found that IL-6 production by T cells is dependent on macrophages, and IL-6 is one of essential factors for pokeweed mitogen induced immunoglobulin production. Both high- and low-affinity IL-6 receptors were identified. The molecular cloning of IL-6 receptors demonstrated that this receptor is a member of the immunoglobulin superfamily. The deregulated production of IL-6 is suggested to be involved in the pathogenesis of autoimmune diseases and in the development of multiple myeloma.

Three interleukms with distinct functions, IL-4, IL-5 and IL-6, are involved in the regulation of B cell response into antibody producing cells. The studies with recombinant interleukins, however, demonstrated that the activities of these interleukins were not restricted to B lineage cells but showed a wide variety of biological functions on various tissues and cells. One of the most typical example of multifunctional interleukins is IL-6. It acts not only on B cells as B cell differentiation factor but also on T cells, hematopoietic stem cells, hepatocytes, nerve cells and myeloma cells. Deregulation of the expression of these interleukins was shown to be responsible for various diseases, such as i) IL-4 vs. immediate type hypersensitivity and ii) IL-6 vs. autoimmunity and multiple myelomas.

Interleukin-6 (IL-6/BSF-2/IFNβ 2) is a multifunctional cytokine that regulates the growth and differentiation of various tissues, and is known particularly for its role in the immune response and acute phase reactions. A complementary DNA encoding the human IL-6 receptor (IL-6-R) has now been isolated. The IL-6-R consists of 468 amino acids, including a signal peptide of ∼19 amino acids and a domain of ∼90 amino acids that is similar to a domain in the immunoglobulin (Ig) superfamily. The cytoplasmic domain of ∼82 amino acids lacks a tyrosine/kinase domain, unlike other growth factor receptors.