The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.

/pdf/regulation-of-type-i-interferon-responses-3z69skuw9f.pdf

Regulation of type I interferon responses

Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.

IDO expression by dendritic cells: tolerance and tryptophan catabolism.

Background Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one ...

https://www.nejm.org/doi/suppl/10.1056/NEJMoa1908639/suppl_file/nejmoa1908639_appendix.pdf

Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

The hormone relaxin is important in female reproduction for embryo implantation, cardiovascular function, and during labor and lactation. Relaxin is also synthesized in males by organs of the male tract. We hypothesized that relaxin might be one component of seminal plasma responsible for eliciting the female cytokine response induced in the uterus at mating. When recombinant relaxin was injected into the uterus of wild-type (Rln+/+) mice at estrus, it evoked the production of Cxcl1 mRNA and its secreted protein product CXCL1 in four of eight animals. Mating experiments were then conducted using mice with a null mutation in the relaxin gene (Rln−/− mice). qRT-PCR analysis of mRNA expression in wild-type females showed diminished uterine expression of several cytokine and chemokine genes in the absence of male relaxin. Similar differences were also noted comparing Rln−/− and Rln+/+ females mated to wild-type males. Quantification of uterine luminal fluid cytokine content confirmed that male relaxin provokes the production of CXCL10 and CSF3 in Rln+/+ females. Differences were also seen comparing Rln−/− and Rln+/+ females mated with Rln−/− males for CXCL1, CSF3, and CCL5, implying that endogenous relaxin in females might prime the uterus to respond appropriately to seminal fluid at coitus. Finally, pan-leukocyte CD45 mRNA was increased in wild-type matings compared to other combinations, implying that male and female relaxin may trigger leukocyte expansion in the uterus. We conclude that male and/or female relaxin may be important in activating the uterine cytokine/chemokine network required to initiate maternal immune adaptation to pregnancy.

/pdf/male-seminal-relaxin-contributes-to-induction-of-the-post-3fdia1cdmv.pdf

Male Seminal Relaxin Contributes to Induction of the Post-mating Cytokine Response in the Female Mouse Uterus

Early embryos are adaptive to the environment they encounter during development and this facilitates embryo resilience to environmental insults. However, it is clear from findings in nonhuman species that adaptive plasticity during early development can have adverse consequences manifesting over the long-term in formation of the post-natal and adult phenotype, and that this occurs via partially characterized programming phenomena. Environmental effectors resulting in adaptive changes to embryos discovered to date include amino acid nutrition, oxygen concentration (both hypoxic and hyperoxic) and growth factor exposure. Other environmental factors known to influence programming of early development have yet to be fully evaluated for their long-term consequences, an area which still requires much work. The mechanisms involved in translation of environmental adaptations to long-term programming are only now being elucidated. Epigenetic mechanisms, especially DNA methylation of imprinted genes, have been associated with adaptive responses to altered environments. Other proposed mechanisms involve temporal gene expression patterns perturbed at critical events during development, such as implantation and early placental morphogenesis. The contribution of programming in early embryos to phenotypic variation and, more importantly, potential health status of resulting offspring has particular relevance to health and diet at the time of conception and to children born following assisted reproductive technologies, especially where embryonic manipulations in artificial environments are involved.

Adaptive responses of early embryos to their microenvironment and consequences for post-implantation development

Cytokines: Pivotal regulators of endometrial immunobiology

Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor beta1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2; however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (approximately 150 microg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum; however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.

Exogenous transforming growth factor beta1 replacement and fertility in male Tgfb1 null mutant mice

Potential role of seminal plasma TGFβ, in the initiation of the post-coital inflammatory response in humans

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