Interferon-γ is a master checkpoint regulator of cytokine-induced differentiation

Abstract

Cytokines are protein mediators that are known to be involved in many biological processes, including cell growth, survival, inflammation, and development. To study their regulation, we generated a library of 209 different cytokines. This was used in a combinatorial format to study the effects of cytokines on each other, with particular reference to the control of differentiation. This study showed that IFN-γ is a master checkpoint regulator for many cytokines. It operates via an autocrine mechanism to elevate STAT1 and induce internalization of gp130, a common component of many heterodimeric cytokine receptors. This targeting of a receptor subunit that is common to all members of an otherwise diverse family solves the problem of how a master regulator can control so many diverse receptors. When one adds an autocrine mechanism, fine control at the level of individual cells is achieved.A s our understanding of physiology grows, we are increasingly aware of its Newtonian aspects in that for every action there is another reaction with opposite consequences (1). Irrespective of whether one thinks in terms of homeostasis, feedback loops, or checkpoints, we increasingly uncover molecular systems that, in terms of function, induce cells to move in opposite ways. For example, although immune T-cell activation is critical in controlling disease, one needs a checkpoint to guard against overactivity that could result in autoimmunity (2, 3).In addition to adding to our general knowledge of cellular physiology, detailed understanding of the molecular mechanisms of activation and checkpoint processes has important therapeutic implications. Such an understanding allows two separate entry points into the regulation of cellular events. Thus, if one wants to promote a cellular function, the same outcome can be achieved by either enhancing the effector or inhibiting the checkpoint pathways, usually by perturbing the molecules that initiate them.One of the most important physiological systems is the cytokine cascade (4). However, here, because the cascade contains large numbers of separate molecules, each operating through different receptors, simple models of regulation break down. While one can imagine that each cytokine is paired with a separate checkpoint system operating in an opposite direction, it seemed to us to be unlikely, if for no other reason than the economical use of genetic information. Given that one had large sets of related molecules with overlapping signal transduction mechanisms and pathways, it seemed more reasonable to assume that, depending on the circumstance, some members of the cytokine repertoire regulate other members of the repertoire. This differs from situations such as PD-1, where the checkpoint mechanistic cascade differs completely from the activation mechanism. By contrast, we propose that cytokine members of a family regulate each other by perturbing common molecular mechanisms. Thus, if gene action economy is proposed for a family, its hallmark should be that some of the same molecules used for...

Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients

“… 47 IFN-γ induces the expression of PD-L1, through increasing STAT1 signaling and decreasing STAT3 activation. 48 IFN-γ can also upregulate the expression of other immune suppressive molecules. 49 In our study we found a strong positive correlation of IFNG with STAT1 mRNA expression, while in both cohorts, a strong correlation was detected between IFNG and the immune suppressive molecule CTLA4.…”

The Dual Nature of Type I and Type II Interferons

“…Ribechini et al found that GM-CSF altered the signaling pathway of IFN-γ allowing it to differentiate monocytes into MDSCs ( 92 ). In a recent article by Zha et al they found that IFN-γ was able to suppress the functions of gp130 cytokines, particularly the ability of OSM, to differentiate mesenchymal stem cells through the upregulation of STAT1, concomitant decrease in STAT3 activation, and internalization of the gp130 receptor ( 95 ). Thus, IFN-γ can both be altered by additional cytokine signaling as well as regulate the signaling pathways of other cytokines.…”

Interferon status as a method of determination of nonspecific biomarkers of human immunopathology

“…ИФН видоспецифичны, обладают широким спектром свойств, в т.ч. антивирусными, иммунорегуляторными, антипролиферативными свойствами, и участвуют в регуляции экспрессии клеточных генов организма [29,34,47,51]. Все клетки организма в той или иной степени обладают способностью вырабатывать ИФН.…”

“…ИФН II типа характеризуется иммунным ИФН-γ [51]. Индукторами ИФН-γ являются Т-клеточные митогены лектины, оксиданты, антилимфоцитарные сыворотки, фрагменты иммуноглобулинов антилимфоцитарных сывороток, специфические антигены и аллоантигены, участвующие в процессе распознавания клеток, большинство микроорганизмов, многие иммуномодуляторы, соли тяжелых металлов.…”