IL-6: from laboratory to bedside

In the late 1960s, the essential role of T-cells in antibody production was reported. This suggested to us that certain molecules should be released from T-cells for the stimulation of B-cells. We discovered activities in the culture supernatant of T-cells that induced proliferation and differentiation of B-cells. The factor that induced B-cells to produce immunoglobulins was named B-cell stimulatory factor (BSF)-2. The complementary DNA that encoded human BSF- 2 was cloned in 1986. Simultaneously, interferon-beta2 and 26-kDa protein in the fibroblasts were independently cloned by different groups and were found to be identical to BSF-2. Later, a hybridoma/plasmacytoma growth factor and a hepatocyte-stimulating factor also were proven to be the same molecule as BSF-2. Various names were used for this molecule because of its multiple biological activities, and thereafter, these names were unified as interleukin (IL)-6. Since the discovery of IL-6, rapid progress has been made in understanding its actions, the IL-6 receptor system, and the IL-6 signal transduction mechanism. More importantly, it was involved in numerous diseases, such as rheumatoid arthritis and Castleman's disease. By accumulating the basic knowledge, a new therapeutic approach by blocking IL-6 actions appeared to be feasible for chronic inflammatory diseases.     

CR-mammography with pixel size of 50 microm and dual-sided reading system: effect of the oblique incident of the X-ray beam on imaging properties and detection

In mammography units, the X-ray tube focal spot is located directly above the chest wall edge of the detector. Therefore, the X-ray beam is incident at a different angle along the cathode-anode axis. When the X-ray beam is incident on the imaging plate (IP) at a relatively large angle, the resolution property of a new imaging plate with dual-sided reading system would be degraded compared with the conventional imaging plate because of the parallax effect, which produces a shift in the image on two sides of the imaging plate. To evaluate the oblique incidence effect of the X-ray beam on the degradation of resolution properties and detection of simulated microcalcifications of a new CR system with a pixel size of 50 microm, its basic imaging properties and observer performance tests were compared with those of a conventional CR system. The resolution properties were evaluated by measuring modulation transfer functions (MTFs). Observer performance tests were conducted to compare the detectability of simulated microcalcifications of CR systems. Degradation of presampling MTFs for the new system is greater than that of the conventional CR system when the X-ray beam was incident at the same angle on the imaging plate. We found that the degradation of the area under the ROC curve (Az) for the new CR system was greater than that of the conventional CR system when the X-ray beam was incident at the same angle on the imaging plate.     

Physical imaging properties and low-contrast performance of a newly developed flat-panel digital radiographic system

We investigated the clinical usefulness of a newly developed flat-panel detector (FPD) system by comparing its physical imaging properties and low-contrast detectability with those of a current FPD system. The newly developed CsI-based indirect FPD (Canon, CXDI-40C) and current Gd(2)O(2)S-based FPD (Canon CXDI-11) systems were used. Characteristic curves, resolution properties, radiographic noise, detective quantum efficiencies (DQEs) and low-contrast detectability for both systems were measured. The new FPD system showed considerably lower noise levels than those of the current FPD system. DQE (0) s of the new and current FPD systems were 75% and 35%, respectively. Observer performance tests of the contrast-detail (C-D) phantom indicated that the new FPD system can significantly improve low-contrast performance over that obtainable with the current FPD system under the same conditions of exposure. The new FPD system provided approximately 50% reduction in exposure while providing comparable detectability. The newly developed FPD system provides radiographic images with excellent inherent physical image quality and low-contrast performance.     

New CR system with pixel size of 50 microm for digital mammography: physical imaging properties and detection of subtle microcalcifications

PURPOSE: To investigate the physical imaging properties and detection of simulated microcalcifications of a new computed radiography (CR) system with a pixel size of 50 microm for digital mammography. MATERIALS AND METHODS: New and conventional CR were employed in this study. The new CR system included a high-resolution imaging plate coupled with the FCR5000MA (50 microm pixel pitch) including transparent support and a dual-sided reader. The conventional CR system was coupled with the FCR9000 (100 microm pixel pitch). Modulation transfer functions (MTFs) and Wiener spectra (WS) of the new and conventional CR systems were measured. Observer performance tests were conducted to compare the effects of pixel size (50 microm vs. 100 microm) on the diagnostic accuracy of CR systems in the detection of simulated microcalcifications. RESULTS: The presampling MTF of the new CR system was higher at high frequencies than the conventional CR system. The WS of the new CR system was comparable to that of the conventional CR system at all frequencies. The area under the receiver operating characteristic (ROC) curve (Az) obtained with the new CR and the conventional CR systems were 0.84 and 0.79, respectively. Results showed that the detection of simulated clustered microcalcifications was significantly improved by use of the new CR system compared with the conventional CR system (p<0.05). CONCLUSION: The new CR mammography system improved physical imaging properties and detection of simulated microcalcifications over conventional CR mammography.     

Hypermethylation associated with inactivation of the SOCS-1 gene,a JAK/STAT inhibitor,in human hepatoblastomas

We recently demonstrated inactivation in hepatocellular carcinomas (HCCs) of the gene encoding SOCS1/JAB1/SSI-1, a JAK-binding protein that regulates the JAK/STAT signal-transduction pathway. In a follow-up immunochemical investigation of expression of SOCS-1 in hepatoblastomas (HBLs), the protein was markedly reduced in half of the HBL tumors we examined. CpG-rich regions upstream of the SOCS-1 gene were hypermehylated in 7 of the 15 HBL cases. The results suggest that hypermethylation may play an important role in silencing the SOCS-1 gene, not only in adult HCCs, but also in liver tumors arising in childhood.     

Usefulness of the opposite direction for Stenvers' method

In otorthinolaryngology, Stenvers' method is employed in radiography of the pyramid (internal acoustic meatus and semicircular canals). However, in cases of dizziness, where the prone position is difficult to achieve, we occasionally use the opposite Stenvers' method instead of the conventional one. This makes it possible to perform radiography with the patient in the supine position. Compared with the conventional Stenvers' method, the problems of this method were increases not only in the rate of magnification but also in lens dose. In this study, we evaluated these problems by employing computed tomography (CT) and a glass dosimeter with phantom as well as by clinical evaluation. The results showed no statistically significant difference between Stenvers' method and the opposite Stenvers' method in both the rate of magnification and the clinical evaluation. The increase in lens dose with the opposite Stenvers' method was not significant. We concluded that the opposite Stenvers' method was useful.     

Anti–interleukin‐6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis

Objective

To investigate whether interleukin‐6 (IL‐6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA).

Methods

Serum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti–IL‐6 receptor monoclonal antibody (anti–IL‐6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL‐6, IL‐1β, and/or tumor necrosis factor α (TNFα) was measured. The inhibitory effect of anti–IL‐6R mAb, recombinant IL‐1 receptor antagonist (IL‐1Ra), and anti‐TNFα mAb on VEGF production was also examined.

Results

Serum VEGF levels in RA patients before anti–IL‐6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti–IL‐6R mAb normalized serum VEGF levels. In the in vitro study, IL‐6 and IL‐1β each induced a slight amount of VEGF production in synovial cells, but TNFα did not. Although VEGF‐inducing activity of these cytokines was not remarkable when they were added alone, IL‐6 acted synergistically with IL‐1β or TNFα to induce VEGF production. There was no synergistic effect between IL‐1β and TNFα. In the presence of all of these cytokines, anti–IL‐6R mAb eliminated the synergistic effect of IL‐6, IL‐1β, and TNFα, while IL‐1Ra or anti‐TNFα mAb did not.

Conclusion

Anti–IL‐6R mAb therapy reduced VEGF production in RA. IL‐6 is the pivotal cytokine that induces VEGF production in synergy with IL‐1β or TNFα, and this may be the mechanism by which IL‐6 blockade effectively suppresses VEGF production in synovial fibroblasts.

     

Postnatally Induced Inactivation of gp130 in Mice Results in Neurological,Cardiac, Hematopoietic,Immunological, Hepatic,and Pulmonary Defects

The pleiotrophic but overlapping functions of the cytokine family that includes interleukin (IL)-6, IL-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin 1 are mediated by the cytokine receptor subunit gp130 as the common signal transducer. Although mice lacking individual members of this family display only mild phenotypes, animals lacking gp130 are not viable. To assess the collective role of this cytokine family, we inducibly inactivated gp130 via Cre-loxP–mediated recombination in vivo. Such conditional mutant mice exhibited neurological, cardiac, hematopoietic, immunological, hepatic, and pulmonary defects, demonstrating the widespread importance of gp130-dependent cytokines.     

An experimental study of conductive heating using a concentric double-electrode applicator

With hyperthermia for treatment of superficial tumors in mind, a prototype applicator with two electrodes arranged concentrically on a disk was designed for efficient local heating, and a basic heating test was carried out. Frequencies as low as 200 kHz were used in order to simplify the configuration of the power device. The applicator consists of two electrodes, a circular inner electrode and another looped outer electrode, arranged concentrically. Water was passed through the applicator as a cooling mechanism; it was placed in direct contact with the target tissue to be heated and then charged with electricity. In the heating test using a phantom, oval hot spots were noted below the inner electrode. Using cooling water at 3°C and 8.2 W, an isothermal line of 45°C was located at a 5-mm radius circle around the central axis with 9 mm depth. A similar temperature distribution map was obtained in heating tests on the thigh muscle of a mongrel adult dog. The temperature distribution maps obtained from these tests corresponded closely with the results of theoretical analysis carried out according to the finite-element method. Since a comparatively low frequency was employed for this applicator the power device was simplified, which made adequate heating possible with low electric power. The temperature distribution map indicated that efficient local heating of superficial tumors could be achieved.     

Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism

Although an immunoregulatory role of aryl hydrocarbon receptor (Ahr) has been demonstrated in T cells and macrophages, little is known about its function in dendritic cells (DC). Here, we show that lipopolysaccharide (LPS) and CpG stimulate Ahr expression in bone marrow-derived dendritic cells (BMDC). Furthermore, we found that Ahr is required to induce indoleamine 2,3-dioxygenase (IDO) expression, an immunosuppressive enzyme that catabolizes tryptophan into kynurenine (Kyn) and other metabolites in DC. In the presence of LPS or CpG, Ahr-deficient (Ahr(-/-)) mature BMDC induced immune responses characterized by reduced Kyn and IL-10 production compared with results observed with tolerogenic mature WT BMDC. In a coculture system with LPS- or CpG-stimulated BMDC and naive T cells, Ahr(-/-) BMDC inhibited naive T-cell differentiation into regulatory T (Treg) cells, which likely facilitated Th17 cell development and promoted naive T-cell proliferation. Addition of synthetic L-Kyn to the coculture system skewed the differentiation of naive T cells to Treg cells rather than Th17 cells. Taken together, our results demonstrate a previously unknown negatively regulatory role for Ahr in DC-mediated immunogenesis in the presence of LPS or CpG, which, in turn, alters the Kyn-dependent generation of Treg cells and Th17 cells from naive T cells.