ABSTRACT
We investigated the role of the TNF receptors, type I (p55TNFR) and type II (p75TNFR), in a mouse model of contact hypersensitivity, i.e., a model of a delayed type hypersensitivity (DTH) allergic reaction. Mice deficient for p55TNFR or p75TNFR were used to investigate the functions of these receptors in development of the DTH reaction. We show that both TNF receptors have a strong influence on the overall outcome of the DTH reaction, with the two TNF receptors exerting distinct functions. Dendritic cells of mice lacking p55TNFR had a defect in allergen uptake but showed normal migration into regional lymph nodes. In contrast, dendritic cells of p75TNFR-deficient mice showed diminished migration into regional lymph nodes after allergen contact, whereas the allergen uptake was independent of the p75TNFR. Thus, both TNF receptors are required for the development of a complete DTH reaction.
Subject(s)
Antigens, CD/metabolism , Dermatitis, Allergic Contact/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Animals , Mice , Mice, Inbred C57BL , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type IIABSTRACT
CD137 (ILA/4-1BB), a member of the TNF receptor family, regulates activation, survival and proliferation of primary human monocytes. Here we compare the activities of lipopolysaccharide (LPS), a classical and potent monocyte activator to that of CD137. LPS is a more potent activator of monocytes, as evidenced by a stronger induction of the proinflammatory cytokine IL-8. However, CD137 could further increase maximal cytokine induction by LPS, which points to separate signaling pathways for LPS and CD137. Also, expression of myc was only induced by the combination of CD137 and LPS. Expression of macrophage colony-stimulating factor is induced more potently by CD137, but an additive effect is obtained by the combination of CD137 and LPS. Monocyte/macrophage survival and proliferation is only induced by CD137. LPS counteracts both activities of CD137 via activation induced cell death. While LPS has a role in activation of monocytes in innate immunity, the CD137 receptor/ligand system seems to deliver an activating signal to monocyte in acquired immunity.
Subject(s)
Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Monocytes/cytology , Monocytes/drug effects , Receptors, Nerve Growth Factor/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Antigens, CD , Apoptosis/drug effects , Cell Adhesion/drug effects , Cell Division/drug effects , Cell Survival/drug effects , Cells, Cultured , Gene Expression Regulation/drug effects , Genes, myc/genetics , Humans , Interleukin-8/metabolism , Macrophage Colony-Stimulating Factor/metabolism , Monocytes/immunology , Monocytes/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Nerve Growth Factor/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , Recombinant Fusion Proteins/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor Receptor Superfamily, Member 9ABSTRACT
Tumor necrosis factor (TNF) mediates its biological effects by binding to two distinct but homologous receptor molecules. The type 1 receptor (TNF-R1) has been shown to be essential and sufficient for most cellular responses to soluble TNF. In contrast, only limited data exist concerning the role of the type 2 receptor (TNF-R2) in TNF responses, both in vitro and in vivo. Here, we demonstrate by the use of thymocytes from TNF-R-deficient mice that the TNF-R2-dependent enhancement of proliferation and secretion of granulocyte-macrophage colony-stimulating factor is in fact mediated by TNF-R2 on its own, independent of co-expression and/or stimulation of TNF-R1.
Subject(s)
Antigens, CD/physiology , Lymphocyte Activation , Receptors, Tumor Necrosis Factor/physiology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/pharmacology , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Concanavalin A/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Humans , Mice , Mice, Knockout , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/metabolism , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type II , Recombinant Proteins/pharmacology , T-Lymphocytes/metabolism , Thymus Gland/cytologyABSTRACT
3 groups (6 control persons, 6 patients with liver cirrhosis, 6 patients with diabetes mellitus) were infused with 20% (w/v) carbohydrate mixture (glucose/fructose/xylitol, 1:2:1) for 48 hours. The metabolical status was controlled in defined intervals by means of 39 different laboratory parameters. The infusion rate was supposed to be 0.25 g carbohydrates/kg B. W. and hour. There were no significant changes in blood glucose levels in any of the 3 groups. However we could observe a slight but constant increase in lactate and triglyceride concentrations. Free fatty acids and keton bodies were suppressed on a low level. Only the diabetics showed a significant renal carbohydrate loss with up to 15% of the amount administered. No clinically relevant side effects were observed.
