Soluble forms of cytokine and growth factor receptors: mechanisms of generation and modes of action in the regulation of local and systemic inflammation

Cytokine and growth factor receptors are usually transmembrane proteins, but they can also exist in soluble forms, either through cleavage and release of their ligand-binding extracellular domain or through the secretion of a soluble isoform. As an extension of this concept, transmembrane receptors on exosomes released into the circulation may act similarly to circulating soluble receptors. These soluble receptors add to the complexity of cytokine and growth factor signalling: they can function as decoy receptor that compete for ligand binding with their respective membrane-bound forms thereby attenuating signalling, or stabilize their ligands, or activate additional signalling events through interactions with other cell-surface proteins. Their soluble nature allows for a functional role away from the production sites, in remote cell types and organs. Accumulating evidence demonstrates that soluble receptors participate in the regulation and orchestration of various key cellular processes, particularly inflammatory responses. In this review, we will discuss release mechanisms of soluble cytokine and growth factor receptors, their mechanisms of action and strategies for targeting their pathways in disease.