Molecular and cellular factors determining the functional pleiotropy of cytokines

Abstract

Cytokines are soluble factors vital for mammalian physiology. Cytokines elicit highly pleiotropic activities, characterized by their ability to induce a wide spectrum of functional responses in a diverse range of cell subsets, which makes their study very challenging. Cytokines activate signalling via receptor dimerization/oligomerization, triggering activation of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway. Given the strong crosstalk and shared usage of key components of cytokine signalling pathways, a long-standing question in the field pertains to how functional diversity is achieved by cytokines. Here, we discuss how biophysicalfor example, ligand-receptor binding affinity and topologyand cellularfor example, receptor, JAK and STAT protein levels, endosomal compartmentparameters contribute to the modulation and diversification of cytokine responses. We review how these parameters ultimately converge into a common mechanism to fine-tune cytokine signalling that involves the control of the number of Tyr residues phosphorylated in the receptor intracellular domain upon cytokine stimulation. This results in different kinetics of STAT activation, and induction of specific gene expression programs, ensuring the generation of functional diversity by cytokines using a limited set of signalling intermediaries. We describe how these first principles of cytokine signalling have been exploited using protein engineering to design cytokine variants with more specific and less toxic responses for immunotherapy.

Pleiotropic immunoregulation by growth‐blocking peptide in Ostrinia furnacalis

“…Second, they display functional redundancy, where groups of cytokines have overlapping activities. These two features make the study of cytokines highly complex (McFarlane et al, 2023). Considering that the insect cytokine GBP is involved in metabolism and immunity, it is worth exploring whether it can regulate the immune response via long‐term effects on metabolism.…”

Compact Programmable Control of Protein Secretion in Mammalian Cells

“…In addition to implementing Boolean logic, it would be advantageous to use the compRELEASE suite to enable more core circuit functions, such as analog signal filtering 46 . Considering some intercellular signals such as cytokines and growth factors have pleiotropic activity based on their concentrations [47][48][49] , the ability to selectively respond to specific concentrations ranges of inputs would be critical for enabling future biomedical therapies. Proteolytic activation and repression of protein secretion within the compRELEASE suite are dependent on cleavage efficiencies of the protease cut sites, which can be manipulated by changing the canonical amino acid sequence (Fig.…”

Differential functional coupling in Gp130-JAK complexes expands the plasticity of the interleukin-6 signaling axis

“…Deregulation of cytokines or cytokine-induced signaling networks often results in disease, making this family highly relevant for human health (4,5). Cytokines of the class I/II family dimerize/oligomerize cell surface receptors to trigger the activation of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signaling pathway but can also control the activity of diverse serine/threonine kinase signaling networks (6,7). The canonical view of cytokine signaling describes a linear process where upon formation of the cytokine-receptor complex, JAKs are activated via transphosphorylation and drive the phosphorylation of Tyr residues in the cytokine receptor intracellular domain (7)(8)(9)(10).…”

“…In most cases, specific JAKs are assigned to each cytokine receptor subunit, which typically promote the activation of a set of defined STAT members to exert unique responses (11). In recent years, however, it has become apparent that cytokine signaling is a more dynamic and plastic process that allows cells to adapt their responses to the changing environment (6). STATs compete for binding to shared pTyr motifs in the cytokine receptor intracellular domains (13).…”