Control of the production of soluble interleukin-4 receptors: implications in immunoregulation

Abstract

Soluble cytokine receptors (sCR) are generated in vivo through proteolytic cleavage of the membrane-bound receptors or by direct translation of mRNAs specifically encoding the soluble forms. Despite their widespread presence in biological fluids, the physiological role of endogenous sCR as immunoregulatory molecules is not yet well understood. In vivo, exogenous soluble interleukin-4 receptors (sIL-4R) have been shown to have both agonistic and antagonistic effects on IL-4 responses, depending on the relative concentration ratios of sIL-4R to IL-4. In an effort to elucidate the potential role of endogenous sIL-4R in the regulation of IL-4 responses, the mechanisms controlling the production of sIL-4R have been investigated. Although many cell types are able to constitutively produce low levels, production of sIL-4R is significantly up-regulated in vitro by T cell activation and IL-4. The ability of splenic cells to produce sIL-4R and the serum levels of sIL-4R have consistently been found to be increased during immune responses characterized by T cell activation and IL-4 secretion (Th2 responses). In agreement, clones of Th2, but not Th1, cells were found to significantly up-regulate sIL-4R production following antigenic stimulation. However, the production of sIL-4R by Th2 cells appears to be independent from that of IL-4 and can also be induced by cell contact and/or IL-1-dependent pathways. Taken together, these observations suggest that the production of sIL-4R in vivo is closely associated with the secretion of IL-4, and are consistent with the notion that endogenous sIL-4R are involved in the regulation of IL-4 activity during immune responses.

Molecular Characterization and Functional Analysis of Murine Interleukin 4 Receptor Allotypes

“…First, the reduced neutralizing activity of the newly identified IL-4R allotype could be of importance in situations with a molar excess of the sIL-4R to the ligand (less efficient IL-4 antagonist). Second, during the early phase of a specific T cell response, when the concentrations of IL-4 exceed those of the sIL-4R, the sIL-4R may act as a transport molecule for IL-4 ( 47 ). The higher dissociation rate of the BALB/c sIL-4R allotype could result in a more rapid release of IL-4 in microenvironments with IL-4–responsive cells, prolonging the half-life of IL-4 (transporter function).…”

Trans-presentation: A novel mechanism regulating IL-15 delivery and responses

“…An explanation may be derived from a similar phenomenon that has been observed in the IL-4Rα system. In addition to being expressed on the cell surface, IL-4Rα is also expressed in a soluble form that stabilizes binding of IL-4 to membrane IL-4R complexes (IL-4Rα/γC) when IL-4 is in excess; however, when sIL-4Rα is in excess, sIL-4Rα sequesters IL-4 thus preventing activity [77]. Alternatively, the different activities of sIL-15Rα, agonist versus antagonist, may lie in the source of the protein.…”

Identification of Estrogen-Regulated Genes of Potential Importance for the Regulation of Trabecular Bone Mineral Density

“…In vivo, exogenous sIL-4R has been shown to have both agonistic and antagonistic effects on IL-4 responses, depending on the relative concentration ratios of sIL-4R to IL-4. (66) Although competition with the membrane IL-4R is probably the basis for its inhibitory action, the mechanisms responsible for the potentiation of IL-4 activity are not completely clear but may involve alterations in the half-life and/or biodistribution of IL-4 in vivo. (67) We found that estrogen increases sIL-4R expression in OVX mice and propose that this might be a potential pathway for the preservation of the trabecular BMD.…”