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receptor shedding

This term relates to the ability of cells to cleave off the extracellular domain of a cytokine receptor and to release it into the circulation as a soluble product (see also: ectodomain shedding) (Heaney and Golde, 1998). Shedding itself can be a process that is regulated by other cytokines and requires the participation of enzymes generally referred to as sheddases.

In many instances these cleavage products are still capable of binding their ligands (decoy receptors). They can neutralize, therefore, freely circulating cytokines and thus allow establishment of retrocrine modes of growth control. The remaining portion of the membrane-bound receptor does not bind ligands any longer and hence the cells may become (transiently) desensibilised to the action of a particular cytokine. On the other hand, soluble receptors can bind their ligands, stabilize them, and may induce cellular responses by association with signaling receptor subunits expressed by target cells, thus acting as an cytokine agonist (see also: trans-signaling).

Such soluble receptors have been described for a variety of cytokines, growth factors, and other receptors, including, for example, IL2, IL4, IL6, IL7, IL11, IL17, IGF, TNF-alpha (see also: TNF-BF, TNF blocking factor) CNTF, IFN-gamma, VEGF, growth hormone, transferrin. The presence of such soluble receptors may introduce errors in cytokine assays and bioassays due to their inherent bioactivities.

Receptor shedding constitutes a further level of cytokine control mechanisms, allowing their activities to be attenuated and fine-tuned in vivo by regulating the amplitude and duration of cytokine signals through competition for the ligand with the cell-bound receptor.

Receptor shedding may be of physiological importance because elevated levels of circulating cytokines as are observed, for example, during shock and the acute phase reaction could be neutralized, at least in part, by capturing cytokines through their soluble receptors. Administration of such receptor fragments might be a novel way to counteract the life-threatening complications of an endotoxemia (see also: Cytokine inhibitors). Impaired shedding of the TNF-alpha receptor has been shown to be responsible for TRAPS, a syndrome characterized by unexplained episodes of fever and severe localized inflammation.

For a regulatory protein involved in receptor shedding see also: ARTS-1 [aminopeptidase regulator of TNFR1 shedding].

LAST MODIFIED: January 2005

See REFERENCES for entry receptor shedding

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