Shunji Miki

Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas.

Interleukin‐6 (IL‐6) was found to be a growth factor of renal cell carcinomas. Furthermore, renal cell carcinomas freshly isolated from the patients expressed mRNA of IL‐6 and secreted biologically active IL‐6 under the culture conditions where the tumor cells could grow, but they did not produce IL‐6 nor proliferate in the absence of fetal calf serum. The production of IL‐6 by the tumor cells was also demonstrated by immunostaining of the IL‐6‐producing cells utilizing anti‐IL‐6 antiserum. Moreover, anti‐IL‐6 antiserum specifically inhibited the in vitro tumor growth. All data indicated that IL‐6 functions as an in vitro autocrine growth factor of renal cell carcinomas.

Functional and possible physical association of scavenger receptor with cytoplasmic tyrosine kinase Lyn in monocytic THP-1-derived macrophages

Acetyl LDL (modified low‐density lipoprotein), which is thought to be taken up through scavenger receptor A (SR‐A), rapidly induced the appearance of phosphotyrosine proteins in monocytic THP‐1‐derived macrophages in vitro. The two alternative forms of Lyn (p53 and p56) were found to be tyrosine‐phosphorylated within 30 s after the stimulation with acetyl LDL. The catalytic activity of Lyn measured by an in vitro kinase assay had also increased in acetyl LDL‐stimulated THP‐1‐derived macrophages. Furthermore, Lyn could be co‐immunoprecipitated with SR‐A from the cell lysate. These observations suggest a functional and possible physical association of SR‐A with Lyn in THP‐1‐derived macrophages, and also imply a possible involvement of Lyn in SR‐A signal transduction.

Masked early symptoms of pneumonia in patients with rheumatoid arthritis during tocilizumab treatment: a report of two cases

Although reports of serious infections in clinical trials for rheumatoid arthritis (RA) with tocilizumab, anti-interleukin6 (IL-6) receptor antibody, have been relatively few, there is still some concern about infections. We report here two cases of patients who developed severe pneumonia during tocilizumab treatment for RA. Both patients initially presented with only minimal clinical symptoms and modest elevations in serum C-reactive protein. Tocilizumab might suppress the early inflammatory symptoms of pneumonia.

Synthesis and structural characterization of triple-helical peptides which mimic the ligand binding site of the human macrophage scavenger receptor

Abstract A synthetic method for triple-helical peptides was developed. Peptides with and without glutamic acid α-thioester at their N-termini are prepared by the solid-phase method. These peptides are crosslinked at their N-termini one by one to generate trimeric peptides using the activation of the thioester group by silver ions. This method was applied to the synthesis of model peptides, which mimic the binding site of modified low density lipoprotein (LDL) in the human scavenger receptor (SR). These models possessed different spacers, which connect the peptide chains and the crosslinking site. CD and DSC analysis of the peptides revealed that spacer length has a critical effect on the stability of the triple helix.

Reduction of atherosclerosis despite hypercholesterolemia in lyn‐deficient mice fed a high‐fat diet

Oxidation and other modifications of serum low‐density lipoprotein (LDL) are associated with the development of atherosclerosis, and a scavenger receptor and CD40 signalling are also known to play important roles in the process. We previously showed that the Src family protein‐tyrosine kinase Lyn is physically and/or functionally associated with macrophage type‐I and type‐II class‐A scavenger receptors (MSR‐A) and CD40.

Expression of scavenger receptors on renal cell carcinoma cells in vitro.

Messenger RNAs and proteins of scavenger receptor thought to be macrophage specific protein were expressed in renal cell carcinoma (RCC) cells in vitro. Acetyl LDL was taken up into RCC cells and promoted the production of interleukin-6 (IL-6), an in vitro autocrine growth factor to proliferate the cells. These results suggested that RCC cells might have a scavenger pathway which has not yet been demonstrated except for macrophages.

Metformin decreases glycated albumin to glycated haemoglobin ratio in patients with newly diagnosed type 2 diabetes

Background To know whether metformin improves postprandial hyperglycaemia, we examined the effect of metformin on the glycated albumin (GA) to glycated haemoglobin (HbA1c) ratio (GA/HbA1c ratio) in patients with newly diagnosed type 2 diabetes. Methods Metformin and lifestyle interventions were initiated in 18 patients with newly diagnosed type 2 diabetes. Metformin was titrated to 1500 mg/day or maximum-tolerated dose. HbA1c and GA were measured every four weeks up to 24 weeks. Results HbA1c decreased significantly from 9.0 ± 2.1% at baseline to 6.5 ± 0.9% at week 24, and GA decreased significantly from 24.3 ± 8.2% to 16.2 ± 3.1%. The GA/HbA1c ratio decreased significantly from 2.66 ± 0.37 at baseline to 2.47 ± 0.29 at week 24 (P < 0.01), despite that the GA/HbA1c ratio reached a plateau value at week 16. The change in the GA/HbA1c ratio during 24 weeks (ΔGA/HbA1c ratio) was significantly correlated with both baseline HbA1c and GA. Moreover, the ΔGA/HbA1c ratio was significantly correlated with the change in GA during 24 weeks but not with the change in HbA1c. Conclusions Metformin decreased the GA/HbA1c ratio in patients with newly diagnosed type 2 diabetes. This suggests that metformin improves postprandial hyperglycaemia in patients with newly diagnosed type 2 diabetes.

Suicide process of renal cell carcinoma cells encountering mumps virus

Renal cell carcinoma cells produced the substance(s) which killed them (suicide factor(s)) after co‐culture with mumps virus. The suicide factor(s) were heat‐sensitive and were degraded with trypsin. Furthermore, actinomycin D inhibited the production of the substance(s) by cancer cells. Considering these facts, the substance(s) were thought to be protein(s) derived from de novo synthesis in cancer cells. It was demonstrated that renal cell carcinoma cells proliferated with the autocrine loop of interleukin‐6 (IL‐6). Mumps virus almost completely inhibited the IL‐6 production in several hours. Because of these two facts, the suicide process might be initiated in renal cell carcinoma cells after encountering mumps virus, i.e. inhibition or the autocrine growth loop of IL‐6 followed by the induction of an autocrine killing loop of unknown substance(s).

Synthesis and structural characterization of the ligand binding site of macrophage scavenger receptor

The macrophage scavenger receptor (SR) mediates the endocytosis of modified LDLs. These ligands, when incorporated in excess, promote the conversion of macrophages into foam cells, which may result in arterial sclerosis. The modified LDL-binding site in human SR is located in the collagen-like domain (HSR(323-341): Ala-Gly-Arg-Pro-Gly-Asn-SerGly-Pro-Lys-Gly-Gln-Lys-Gly-Glu-Lys-Gly-Ser-Gly) [1]. In the present study, a new synthetic strategy for trimeric peptides was developed and applied to the syntheses of HSR(323-341) models (Fig. 1). The effect of spacer (X) on the structure was characterized by CD.