As an essential metal for sustaining life, iron is involved in a number of metabolic processes, including DNA synthesis, electron transport, oxygen delivery, and so on. Iron metabolism involves the absorption, transport, and use of iron and is strictly regulated. Numerous studies have found a positive correlation between iron storage and the risk of tumors, such as colorectal carcinoma, hepatic cancer, renal carcinoma, lung cancer, and gastric cancer. In tumor cells, iron metabolism changes by several mechanisms, such as regulating the growth of tumor cells by transferrin, accelerating the uptake of iron by the overexpressions of transferrin receptors 1 and 2 (TfR1 and TfR2), synthesizing or secreting ferritin by some malignant tumor cells, and upregulating the level of hepcidin in patients with cancer. Some advances on diagnosis and treatment based on iron metabolism have been achieved, such as increasing the transfection and target efficiency of transferrin-polyethylenimine (PEI), inducing cell apoptosis by beta-guttiferin through interacting with TfR1.
Animals ; Antibiotics, Antineoplastic ; pharmacology ; Antigens, CD ; genetics ; metabolism ; Antimicrobial Cationic Peptides ; biosynthesis ; genetics ; Apoptosis ; Cell Proliferation ; Doxorubicin ; pharmacology ; Ferritins ; metabolism ; physiology ; Hepcidins ; Humans ; Interleukin-18 ; pharmacology ; Iron ; metabolism ; physiology ; Neoplasms ; metabolism ; pathology ; RNA, Messenger ; metabolism ; Receptors, Transferrin ; genetics ; metabolism ; Transferrin ; metabolism ; physiology ; Tumor Suppressor Protein p53 ; pharmacology

OBJECTIVETo examine serum concentration of interleukin-18 (IL-18) and IL-18 mRNA expression in peripheral blood mononuclear cells (PBMCs) in children with primary nephrotic syndrome (PNS) and explore the possible role of IL-18 in steroid-resistant nephrotic syndrome (SRNS).

METHODSSixty-six children with newly diagnosed PNS, including 39 cases of steroid sensitive nephrotic syndrome (SSNS) and 27 cases of SRNS, were enrolled. Forty healthy children were used as a normal control group. Blood samples were collected before and 8 weeks after glucocorticoid treatment. Serum concentration of IL-18 was measured using ELISA. IL-18 mRNA expression in PBMCs was detected by the RT-PCR method. The amount of 24-hr urine protein was measured by the biuret method. Serum contents of total cholesterol (T-Ch), triglyceride (TG), low density lipoprotein (LDL), total protein (TP), and albumin (Alb) were measured by the automatic biochemistry analyzer.

RESULTSSerum concentration of IL-18 and IL-18 mRNA expression in PBMCs in the SSNS and the SRNS groups were significantly higher than those in the normal control group before treatment (P< 0.05). The SRNS group had increased serum protein concentration of IL-18 and IL-18 mRNA expression in PBMCs compared with the SSNS group before treatment (P< 0.05). Serum LDL content in the SRNS group was also significantly higher than that in the SSNS group before treatment (P< 0.05). After treatment, serum concentration of IL-18 and IL-18 mRNA expression in PBMCs in the SRNS group were significantly higher than those in the SSNS and the normal control groups (P< 0.05). Serum concentration of IL-18 and IL-18 mRNA expression in PBMCs in the SSNS group were significantly reduced after treatment, but the alterations of IL-18 were not observed in the SRNS group after treatment.

CONCLUSIONSSRNS was associated with increased serum IL-18 concentration and IL-18 mRNA expression in PBMCs. Over-production of IL-18 may play a role in the development of SRNS.

Adolescent ; Adrenal Cortex Hormones ; therapeutic use ; Child ; Child, Preschool ; Drug Resistance ; Female ; Humans ; Interleukin-18 ; blood ; genetics ; physiology ; Leukocytes, Mononuclear ; metabolism ; Lipoproteins, LDL ; blood ; Male ; Nephrotic Syndrome ; blood ; drug therapy ; RNA, Messenger ; blood

OBJECTIVE: To investigate the role of cathepsin B in hepatic Kupffer cells (KCs) in activating Toll-like receptor 4(TLR- 4)-independent inflammatory pathways in mice with lipopolysaccharide (LPS)-induced sepsis. METHODS: Eighteen wild-type (WT) mice and 18 TLR4-knockout (TLR4) mice were both divided into 3 groups for intraperitoneal injections of a lethal dose (54 mg/kg) of LPS, LPS and CA-074(a cathepsin B inhibitor), or normal saline, and the survival of the mice were observed. Another 36 WT mice and 36 TLR4mice were also divided into 3 groups and subjected to intraperitoneal injections of normal saline, 20 mg/kg LPS, or LPS with CA-074 pretreatment.After the treatments, KCs were collected from the mice for assessing the protein level and activity of cathepsin B.The histopathological changes of the liver were observed with HE staining, and the serum levels of IL-1α, IL-1β, TNF-α and IL-18 were detected. RESULTS: Compared with the WT mice,TLR4mice receiving the lethal dose of LPS had significantly longer survival time (up to 84 h) after the injection,but were still unable to fully resist LPS challenge.CA-074 pretreatment prolonged the survival time of WT mice and TLR4mice to 60 h and 132 h,respectively.In the mouse models of sepsis,20 mg/kg LPS induced significantly enhanced activity of cathepsin B without affecting its expression level in the KCs (<0.05) and increased the serum levels of the inflammatory cytokines.CA-074 pretreatment of the mice obviously lessened the detrimental effects of LPS in TLR4mice by significantly lowering cathepsin B activity in the KCs,alleviating hepatocyte apoptosis and reducing the serum levels of inflammatory cytokines. CONCLUSIONS Cathepsin B plays an important role in activating TLR4-independent inflammatory pathways in mice with LPS-induced sepsis.
Animals ; Cathepsin B ; antagonists & inhibitors ; physiology ; Dipeptides ; pharmacology ; Gene Knockout Techniques ; Hepatocytes ; Inflammation ; metabolism ; Interleukin-18 ; blood ; Interleukin-1alpha ; blood ; Interleukin-1beta ; blood ; Kupffer Cells ; metabolism ; Lipopolysaccharides ; Liver ; pathology ; Mice ; Sepsis ; etiology ; metabolism ; Toll-Like Receptor 4 ; genetics ; Tumor Necrosis Factor-alpha ; blood

Xenotransplantation, the transplantation of cells, tissues or organs between individuals of different species, would resolve the current shortage of organs, but rejection remains the major hurdle to successful xenotransplantation. In the present study, we analyzed mixed lymphocyte reactions (MLRs) and used 51Cr release assays in order to identify the proliferation and expansion of mouse CD8+ cytotoxic T lymphocyte cells against PK15, PK15/pIL-18 or PK15/mIL-18 cells. In addition, we identified T cell populations in mouse splenocytes and lymph node cells using two-color flow cytometry. It was found that the CD8+T cells of xenograft recipients proliferated extensively and that the survival rates of populations of PK15/mIL-18 or PK15/pIL-18 cells were higher than untransfected controls. Moreover, CD3+T cells were increased in mice injected with PK15 cells or PK15/pIL-18 cells but PK15/pIL-18 cell numbers were lower in lymph nodes than untransfected controls. CD8+T cells numbers were reduced in the lymph nodes of PK15/pIL-18 injected mice. These results suggest that porcine IL-18 regulates anti-pig cellular rejection in C57BL/6 mice.
Transplantation, Heterologous ; Transplantation ; Transgenes/immunology/physiology ; Transfection ; Tissue Distribution ; T-Lymphocytes/metabolism ; Swine ; RNA, Messenger/metabolism ; Phenotype ; Mice, Inbred C57BL ; Mice ; Lymphocyte Culture Test, Mixed ; Lymphocyte Activation ; Kidney/cytology/*immunology ; Interleukin-18/*genetics/metabolism/physiology ; Immunosuppression/*methods ; Graft Rejection/immunology/*prevention & control ; Genetic Vectors/chemical synthesis ; Female ; Epithelial Cells/*drug effects/*transplantation ; Cytokines/metabolism ; Cells, Cultured ; Animals