Interferon-gamma (IFN-gamma) coordinates a diverse array of cellular programs through transcriptional regulation of immunologically relevant genes. This article reviews the current understanding of IFN-gamma ligand, receptor, signal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophage function during infection. The current model for IFN-gamma signal transduction is discussed, as well as signal regulation and factors conferring signal specificity. Cellular effects of IFN-gamma are described, including up-regulation of pathogen recognition, antigen processing and presentation, the antiviral state, inhibition of cellular proliferation and effects on apoptosis, activation of microbicidal effector functions, immunomodulation, and leukocyte trafficking. In addition, integration of signaling and response with other cytokines and pathogen-associated molecular patterns, such as tumor necrosis factor-alpha, interleukin-4, type I IFNs, and lipopolysaccharide are discussed.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0603252

Interferon-γ: an overview of signals, mechanisms and functions

This article reviews the literature regarding the structure and function of two types of exotoxins expressed by Staphylococcus aureus, pyrogenic toxin superantigens (PTSAgs) and hemolysins. The molecular basis of PTSAg toxicity is presented in the context of two diseases known to be caused by these exotoxins: toxic shock syndrome and staphylococcal food poisoning. The family of staphylococcal PTSAgs presently includes toxic shock syndrome toxin-1 (TSST-1) and most of the staphylococcal enterotoxins (SEs) (SEA, SEB, SEC, SED, SEE, SEG, and SEH). As the name implies, the PTSAgs are multifunctional proteins that invariably exhibit lethal activity, pyrogenicity, superantigenicity, and the capacity to induce lethal hypersensitivity to endotoxin. Other properties exhibited by one or more staphylococcal PTSAgs include emetic activity (SEs) and penetration across mucosal barriers (TSST-1). A detailed review of the molecular mechanisms underlying the toxicity of the staphylococcal hemolysins is also presented.

Exotoxins of Staphylococcus aureus

This review is aimed at providing readers with a comprehensive reference article about the distribution and function of P2 receptors in all the organs, tissues, and cells in the body. Each section provides an account of the early history of purinergic signaling in the organ/cell up to 1994, then summarizes subsequent evidence for the presence of P2X and P2Y receptor subtype mRNA and proteins as well as functional data, all fully referenced. A section is included describing the plasticity of expression of P2 receptors during development and aging as well as in various pathophysiological conditions. Finally, there is some discussion of possible future developments in the purinergic signaling field.

/pdf/cellular-distribution-and-functions-of-p2-receptor-subtypes-32555c8g2p.pdf

Cellular distribution and functions of P2 receptor subtypes in different systems.

Multidisciplinary utilization of dimethyl sulfoxide: pharmacological, cellular, and molecular aspects

https://zenodo.org/record/890801/files/article.pdf

Delivery of bioactive molecules into the cell: the Trojan horse approach

Calcium crystals in osteoarthritic (OA) joints promote enzymatic degradation of articular tissues. Matrix vesicles provide a nidus for calcium crystal formation in chick epiphyseal and mature porcine articular cartilage. In order to examine a potential role for matrix vesicles from OA cartilage in generating pathologic crystals, we sought to determine whether vesicles derived from human OA cartilage (OAMV) could mineralize; and we characterized the resultant mineral species. OAMV were isolated and examined for alkaline phosphatase (AP) and nucleoside triphosphate pyrophosphohydrolase (NTPPPH) activity. OAMV ATP-dependent and independent mineralization were measured in a radiometric biomineralization assay, and newly formed OAMV crystals were examined using Fourier transform infrared spectroscopy (FTIR) and compensated polarized light microscopy. The mean specific activity of OAMV AP was approximately 6 times higher and NTPPPH activity 11 times lower than that of previously characterized, mature, porcine, articular cartilage vesicles. OAMV progressively precipitated 45Ca over time both in the presence and absence of ATP. The FTIR spectra of mineral formed in ATP-dependent assays most closely resembled the standard spectrum for calcium pyrophosphate dihydrate (CPPD). The FTIR spectra of OAMV mineral formed in the absence of ATP closely resembled apatite. These data support the hypothesis that OAMV may form mineral phases of two key crystals found in degenerating cartilage and provide further evidence for the role of matrix vesicles in pathologic articular cartilage biomineralization.

Human osteoarthritic cartilage matrix vesicles generate both calcium pyrophosphate dihydrate and apatite in vitro

Objective. To determine whether adult articular cartilage mineralizes in the presence of ATP.



Methods. Intact adult porcine articular cartilage and monolayers of chondrocytes were cultured in physiologic media containing ATP, and mineralization was measured as retention of 45Ca. Cartilage was analyzed by electron microscopy.



Results. Articular cartilage sequestered 45Ca when incubated with 100 γM ATP. Use of the ATP analog α,β-methylene ATP did not promote mineralization and addition of pyrophosphatase inhibited mineralization, indicating that hydrolysis of ATP to AMP and inorganic pyrophosphate is necessary for the process to occur. Mineral was concentrated in articular cartilage vesicles in the perichondral area.



Conclusion. Adult articular cartilage mineralizes in the presence of ATP, in a manner similar to that found with isolated matrix or articular cartilage vesicles. This supports the notion that these structures have a role in chondrocalcinosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780351216

ATP-induced chondrocalcinosis.

Transport of γ-interferon into the cell nucleus may be mediated by nuclear membrane receptors

Radioiodinated mouse interferon-beta (125I-MuIFN-beta) bound with high affinity (Kd = 9.8 X 10(-10) M) to plasma membrane of L929 murine fibroblasts (4-6 X 10(3) receptor sites per cell). The binding was saturable and inhibited by a 100-fold excess of unlabeled MuIFN-beta but not by excess mouse IFN-gamma (MuIFN-gamma). MuIFN-beta bound at 4 degrees C was very rapidly internalized upon warming of the cells to 37 degrees C (t 1/2 = 1.5 min). Indirect immunoferritin labeling indicated that MuIFN-beta was initially located in coated pits and subsequently internalized by receptor-mediated endocytosis. Isolated L929 cell nuclei bound 125I-MuIFN-beta with a 7-fold higher affinity (Kd = 1.4 X 10(-10) M) and higher receptor density (about 10(4) per nucleus) than that for the plasma membrane. Binding to the nuclear membrane was inhibited by a 100-fold excess of unlabeled MuIFN-beta but not by excess MuIFN-gamma. Trypsin treatment of nuclei decreased IFN binding by 80%, suggesting that the putative nuclear receptors are protein. Specific binding of MuIFN-beta to nuclei was also shown by fluorescence and electron microscopy. We propose that the very rapid internalization of MuIFN-beta by receptor-mediated endocytosis is important in the cellular processing of IFN and that its high-affinity binding to the nuclear membrane suggests the nucleus as an intracellular site of IFN action.

Vladimir M. Kushnaryov

Papers

Human osteoarthritic cartilage matrix vesicles generate both calcium pyrophosphate dihydrate and apatite in vitro

ATP-induced chondrocalcinosis.

Transport of γ-interferon into the cell nucleus may be mediated by nuclear membrane receptors

Murine interferon-beta receptor-mediated endocytosis and nuclear membrane binding.

Transmissible Retrovirus in Epstein-Burr Virus-Producer B95-8 Cells