Fine-Tuning Cytokine Signals

Abstract

Cytokines are secreted or otherwise released polypeptide factors that exert autocrine and/or paracrine actions, with most cytokines acting in the immune and/or hematopoietic system. They are typically pleiotropic, controlling development, cell growth, survival, and/or differentiation. Correspondingly, cytokines are clinically important, and augmenting or attenuating cytokine signals can have deleterious or therapeutic effects. Besides physiological fine-tuning of cytokine signals, altering the nature or potency of the signal can be important in pathophysiological responses and can also provide novel therapeutic approaches. Here, we give an overview of cytokines, their signaling and actions, and the physiological mechanisms and pharmacologic strategies to fine-tune their actions. In particular, the differential utilization of STAT proteins by a single cytokine or by different cytokines and STAT dimerization versus tetramerization are physiological mechanisms of fine-tuning, whereas anticytokine and anticytokine receptor antibodies and cytokines with altered activities, including cytokine superagonists, partial agonists, and antagonists, represent new ways of fine-tuning cytokine signals.

Keywords: STAT protein; STAT tetramerization; cytokine; fine-tuning; partial agonist; superenhancers.

Figure 1

Illustrative signaling pathways for cytokines that are members of different cytokine families. (a) γ_c family cytokines, (b) type I and type II interferons, and (c) IL-17 family cytokines bind to their receptors, activate (a,b) JAK/STAT or (c) ACT1/TRAF6/NF-κB signaling pathways, and initiate cytokine-specific gene expression programs. (a) Of γ_c family cytokines (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21), only IL-2 and IL-15 are shown, and these primarily signal in cis (IL-2) or in trans (IL-15). IL-4, IL-7, IL-9, and IL-21 are only known to signal in cis. In addition to JAK-STAT, MAPK and PI3K pathways are activated. Both STAT5 dimers and STAT5 tetramers are activated by IL-2 and IL-15. (b) Type I interferons (IFN-α/β) activate ISGF3 (STAT1/STAT2/IRF9), whereas type II interferon (IFN-γ) activates STAT1 dimers and tetramers. (c) Signaling via either IL-17RA/IL-17RC or IL-17RA/IL-17RB. The latter is used by IL-17E, which is also known as IL-25. Abbreviations: Co, co-activator (such as CBP or p300); TF, transcription factor; PI3K, phospho-inositol 3-kinase; Pol II, RNA polymerase II.

Figure 2

Fine-tuning cytokine signals by STAT proteins or other cytokines. (a) Multiple STAT proteins activated by a cytokine can determine its overall effect based on the potency of activation of each STAT; this is illustrated by the relative strength of STAT3 versus STAT1 activation by IL-21. (b) Different cytokines can either enhance (blue) or suppress (red) the actions of other cytokines. Abbreviations: Tfh, T follicular helper cell; Th1, T helper type 1 cell.

Figure 3

Fine-tuning cytokine signals by STAT dimers versus tetramers. (a) The essential functions of STAT1 and STAT5 are illustrated by the severe defects observed in mice in which the genes encoding STATs are deleted. (b) STAT tetramers serve critical functions, but the effect of preventing STAT tetramerization is less severe than the phenotype observed with complete deletion of the STAT proteins, indicating that STAT dimers alone can mediate certain core functions. Abbreviations: NK, natural killer; Treg, regulatory T cell.

Figure 4

Rationally fine-tuning cytokine signals. Cytokine signals can be fine-tuned by changing a few amino acids of the cytokine to either promote better binding (superagonist) or diminish the binding (antagonist) of a receptor chain. Fine-tuning can also be achieved by the use of a ligand-receptor complex (e.g., BiG, which is an IL-15–IL-15Rαfusion protein) or antibodies to either cytokines or cytokine receptors. Orthogonal cytokine-cytokine receptor systems can be used to selectively expand a given set of cells. Abbreviations: RLI, receptor linker IL-15; TF, transcription factor.