Hydrolysis of inositol phospholipids by phospholipase C is initiated by either receptor stimulation or opening of Ca2+ channels. This was once thought to be the sole mechanism to produce the diacylglycerol that links extracellular signals to intracellular events through activation of protein kinase C. It is becoming clear that agonist-induced hydrolysis of other membrane phospholipids, particularly choline phospholipids, by phospholipase D and phospholipase A2 may also take part in cell signaling. The products of hydrolysis of these phospholipids may enhance and prolong the activation of protein kinase C. Such prolonged activation of protein kinase C is essential for long-term cellular responses such as cell proliferation and differentiation.

https://science.sciencemag.org/content/sci/258/5082/607.full.pdf

Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C

Interferons play key roles in mediating antiviral and antigrowth responses and in modulating immune response. The main signaling pathways are rapid and direct. They involve tyrosine phosphorylation and activation of signal transducers and activators of transcription factors by Janus tyrosine kinases at the cell membrane, followed by release of signal transducers and activators of transcription and their migration to the nucleus, where they induce the expression of the many gene products that determine the responses. Ancillary pathways are also activated by the interferons, but their effects on cell physiology are less clear. The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interferons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.

http://www3.uah.es/farmamol/Public/AnnReviews/PDF/Biochemistry/Interferons.pdf

How cells respond to interferons

Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

Activators and target genes of Rel/NF-kappaB transcription factors.

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

Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.

Macrophage activation and polarization.

The Cell Biology of Macrophage Activation

https://www.cell.com/imto/pdf/0167-5699(87)90145-9.pdf

Molecular mechanisms of signal transduction in macrophages

Methods for Studying Mononuclear Phagocytes is a practical guide to the study of mononuclear phagocytes that brings together various well-established and useful methods for examining these cells. The technical protocols have been made detailed, specific, practical, and inclusive of the necessary mystique for immediate and direct application in the laboratory. The book is divided into 11 parts arranged according to the sequence of steps that would generally be followed to study a given population of mononuclear phagocytes: (I) methods for obtaining and culturing populations of human and animal mononuclear phagocytes; (II) methods for separating populations of leukocytes to enrich or deplete their content of mononuclear phagocytes; (II) criteria and techniques for identifying mononuclear phagocytes; (IV) methods for quantifying the number of mononuclear phagocytes; (V) techniques for studying the morphology of mononuclear phagocytes; (VI) methods for quantifying the biochemical constituents of mononuclear phagocytes; (VII) methods of quantifying phagocytosis, pinocytosis, and chemotaxis; (VIII) methods for quantifying the secretory products of mononuclear phagocytes; (IX) procedures for quantifying the destruction of tumor cells and of microorganisms by mononuclear phagocytes; (X) methods for studying the cell biology of mononuclear phagocytes; and (XI) techniques for studying mononuclear phagocytes in vivo, including procedures for estimating their kinetics, accumulation, identification, and microbicidal properties.

Methods for studying mononuclear phagocytes

Mononuclear phagocytes constitute a major, host regulatory and efTector system (Adams & Hamilton 1984, 1987, Nathan & Cohn 1980). These highly versatile cells, which populate all tissues in the body, are not only phagocytic but are avid secretory cells and have potent destructive potential toward microbes and neoplastic cells. It has long been appreciated that the function of these phagocytes is not static but rather can be dramatically changed in a variety of circumstances. The modulation of macrophage function by interaction with products from Tlymphocytes has long been considered the prototypic example of such alteration in function. Over the past 5 yr, IFNy has become recognized as the major product from T-cells that alters the function of macrophages. Specially, it has been identified as a principal macrophage activating factor responsible for initiating enhanced competence of macrophages to destroy facultative and obligate intracellular parasites and tumor cells. Actions of IFNy on macrophages are not, however, limited to these effects, since it can also induce competence to present antigen to T-cells, mount an effective respiratory burst, and either enhance or reduce the expression of a wide variety of macrophage proteins. The macrophage, after having entered the tissues, often becomes a relatively quiescent resident cell unless confronted with one or more stimulatory signals in its local environment (Adams & Hamilton 1984, 1987, Nathan & Cohn 1980). In the latter case, it may undergo dramatic changes in functional potential. Mononuclear phagocytes are muitipotential cells and can develop increased function along a variety of disparate paths. Some of these paths represent mutually exclusive routes, such that enhanced competence for one function is usually gained at the expense of diminished competence for another. It is useful to distinguish between complex

Molecular transductional mechanisms by which IFN gamma and other signals regulate macrophage development.

Effector mechanisms of cytolytically activated macrophages. II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neutral proteases.

Dolph O. Adams

Papers

The Cell Biology of Macrophage Activation

Molecular mechanisms of signal transduction in macrophages

Methods for studying mononuclear phagocytes

Molecular transductional mechanisms by which IFN gamma and other signals regulate macrophage development.

Effector mechanisms of cytolytically activated macrophages. II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neutral proteases.