[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

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

Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

Plasminogen activators, tissue degradation, and cancer.

The biochemistry and medical significance of the flavonoids.

Death by apoptosis is characteristic of cells undergoing deletion during embryonic development, T- and B-cell maturation and endocrine-induced atrophy. Apoptosis can be initiated by various agents and may be a result of expression of the oncosuppressor gene p53 (refs 6-8). Here we study the dependence of apoptosis on p53 expression in cells from the thymus cortex. Short-term thymocyte cultures were prepared from mice constitutively heterozygous or homozygous for a deletion in the p53 gene introduced into the germ line after gene targeting. Wild-type thymocytes readily undergo apoptosis after treatment with ionizing radiation, the glucocorticoid methylprednisolone, or etoposide (an inhibitor of topoisomerase II), or after Ca(2+)-dependent activation by phorbol ester and a calcium ionophore. In contrast, homozygous null p53 thymocytes are resistant to induction of apoptosis by radiation or etoposide, but retain normal sensitivity to glucocorticoid and calcium. The time-dependent apoptosis that occurs in untreated cultures is unaffected by p53 status. Cells heterozygous for p53 deletion are partially resistant to radiation and etoposide. Our results show that p53 exerts a significant and dose-dependent effect in the initiation of apoptosis, but only when it is induced by agents that cause DNA-strand breakage.

Thymocyte apoptosis induced by p53-dependent and independent pathways

Toll-like receptors (TLRs) belong to the innate immune system and regulate inflammatory events that affect mammalian reproduction. In Study 1, we demonstrated that abundance of ovine TLR1-TLR9 mRNAs in the uterus differs due to reproductive status (TLR2, TLR3, TLR7, and TLR8) and the day of the estrous cycle and pregnancy (TLR1-TLR3, TLR5-TLR7, and TLR9). Expression of TLR7 and TLR8 proteins was localized primarily to uterine epithelia and stroma and regulated in a temporal manner. In Study 2, we determined that ovine conceptuses express TLR7 and TLR8 on all days studied and that expression of the envelope protein of ovine endogenous retrovirus (enJSRV-Env) declined in conceptus trophectoderm from Day 13 to Day 16 of pregnancy. In Study 3, loss-of-function experiments were conducted in vivo using morpholino antisense oligonucleotides (MAOs) injected into the uterine lumen to block synthesis of TLR7 and TLR8 proteins, individually and jointly. Conceptuses were recovered on Day 16 to assess their morphology. MAO-treated conceptuses were developmentally retarded, produced less interferon tau (IFNT), and had fewer binucleate cells (BNCs) compared with MAO-Controls. Moreover, expression of enJSRV-Env mRNA in MAO-TLR7 conceptuses was greater than that for MAO-Control and MAO-TLR8 conceptuses, but similar to MAO-TLR7/TLR8 conceptuses. Results of this study indicated differences in TLR1-TLR9 expression due to reproductive status and the day of the estrous cycle and pregnancy. TLR7 and TLR8 also influence development, enJSRV-Env abundance, secretion of IFNT, and formation of BNCs by conceptuses. These findings corroborate our hypothesis that TLR7 and TLR8 mediate pathways whereby enJSRV-Env regulates key peri-implantation events in conceptus development and differentiated functions of trophectoderm cells.

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Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep.

I developed a passion for reproductive biology when taking a course in Physiology of Reproduction at Louisiana State University while preparing to apply for Veterinary School at Texas A&M University. My career path changed. I entered graduate school, obtained a Ph.D. and have enjoyed an academic career conducting research in uterine biology and pregnancy in animal science departments at the University of Florida and at Texas A&M University. My contributions to science include: (1) identification of molecules secreted by or transported by uterine epithelia into the uterine lumen that are critical to successful establishment and maintenance of pregnancy, (2) discovery of steroids and proteins required for pregnancy-recognition signalling and their mechanisms of action in pigs and ruminants, (3) patterns of fetal-placental development and placental transport of nutrients, (4) identification of links between nutrients and components of histotroph that affect fetal-placental development, (5) characterising aspects of the endocrinology of pregnancy and (6) contributing to efforts to exploit the therapeutic value of interferon tau, particularly for treatment of autoimmune and inflammatory diseases. Current research focuses on select nutrients in the uterine lumen, specifically amino acids, glucose and fructose, that affect conceptus development, the therapeutic potential for interferon tau, stromal-epithelial cell signalling whereby progesterone and oestrogen act via steroid receptors in uterine stromal cells to stimulate secretion of growth factors (e.g. fibroblast growth factors and hepatocyte growth factor) that regulate uterine epithelial cells and conceptus trophectoderm, and roles of toll-like receptors expressed by uterine epithelia and conceptus trophectoderm in pregnancy.

Contributions of an animal scientist to understanding the biology of the uterus and pregnancy.

Uteroferrin and rose proteins for stimulating hematopoietic cells

Effect of recombinant alpha interferons on fertility and interestrous interval in sheep.

Fibroblast growth factor 2 (FGF2) is a mitogen that induces proliferation, differentiation, and migration of cells, as well as angiogenesis and carcinogenesis via autocrine or paracrine actions. Fibroblast growth factor 2 expression is abundant in porcine conceptuses and endometrium during the estrous cycle and peri-implantation period of pregnancy. However, its intracellular actions in uterine epithelial cells have not been reported. The results of this study indicated abundant expression of FGFR1 and FGFR2 predominantly in uterine luminal and glandular epithelia during early pregnancy and that their expression decreased with increasing parity of the sows. Treatment of porcine uterine luminal epithelial (pLE) cells with FGF2 increased proliferation and DNA replication based on increases in proliferating cell nuclear antigen (PCNA) and initiation of G1/S phase progression. In addition, FGF2 increases phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38, and P90RSK in a time-dependent manner, and increases in their expression was suppressed by Wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), U0126 (an ERK1/2 inhibitor), SP600125 (a JNK inhibitor), and SB203580 (a P38 inhibitor) based on western blot analyses. Also, the abundance of cytoplasmic p-AKT protein was decreased by Wortmannin and U0126, and p-ERK1/2 protein was reduced only by U0126. Furthermore, inhibition of each signal transduction protein reduced the ability of FGF2 to stimulate proliferation and migration of pLE cells. Collectively, these results indicate that activation of FGFR1 and FGFR2 by uterine- and endometrial-derived FGF2 stimulates PI3K/AKT and mitogen-activated protein kinase pathways for development of the porcine uterus and improvement of litter size.

Fuller W. Bazer

Papers

Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep.

Contributions of an animal scientist to understanding the biology of the uterus and pregnancy.

Uteroferrin and rose proteins for stimulating hematopoietic cells

Effect of recombinant alpha interferons on fertility and interestrous interval in sheep.

Stimulatory effects of fibroblast growth factor 2 on proliferation and migration of uterine luminal epithelial cells during early pregnancy