Identification of a Novel IL-6 Isoform Binding to the Endogenous IL-6 Receptor

Abstract

Interleukin (IL)-6 is a multifunctional cytokine showing a wide variety of biologic functions on various tissues. Extracellular IL-6 signals through heterohexameric complex formation with IL-6 receptor-alpha (IL-6Ralpha) and IL-6 receptor-beta (IL-6Rbeta). In analogy to cytokines IL-2 and IL-4, we investigated the expression of IL-6 splice variants in lung tissue and cultivated fibroblasts. In human lung specimens, four different IL-6 transcripts were characterized as follows: native IL-6; IL-6 missing either exon 2 (IL-6Delta2), exon 4 (IL-6Delta4), or missing both; and exons 2 and 4 (IL-6Delta2,4). Only native IL-6 and IL-6Delta4 encoded for proteins of ~ 26 and 17 kD, respectively. Although the overall structure and most functional sites of the IL-6Delta4 protein were predicted to be maintained, IL-6Delta4 was found to lack two amino acids necessary for IL-6/IL-6 homodimerization as well as two of the six amino acids required for interaction with IL-6Rbeta. Receptor mobility shift assays confirmed that the new isoform formed a stable complex with IL-6Ralpha; however, no interaction with IL-6Rbeta was observed. Thus, IL-6Delta4 is likely to compete with native IL-6 for IL-6Ralpha binding but fails to transmit IL-6Rbeta-mediated signaling.

Apobec-1 Complementation Factor Modulates Liver Regeneration by Post-transcriptional Regulation of Interleukin-6 mRNA Stability

“…2A). We entertained the possibility that changes in hepatic IL-6 mRNA expression in Acf ϩ/Ϫ mice might involve differential alternative splicing, similar to what has been observed in other murine tissues (20). However, this was not the case.…”

The co-existence of two growth hormone receptors in teleost fish and their differential signal transduction, tissue distribution and hormonal regulation of expression in seabream

“…This phenomenon of a receptor being attenuated by another related receptor subtype has been observed in a number of cases. These include the estrogen receptor (ER) in which ER was demonstrated to play a role in modulating the effects of ER (Zhang et al 2000), the interleukin (IL)-6 receptor in which the 4 isoform acts as a competitor of ligand binding terminating the cytokine-induced signal transduction (Bihl et al 2002), and the growth hormone secretagog receptor (GHSR) in which the GHSR-1b subtype attenuates the signaling of the GHSR-1a subtype . Whether the same principle applies to sbGHR1 and sbGHR2 here awaits further studies.…”

Widespread shortening of 3’ untranslated regions and increased exon inclusion are evolutionarily conserved features of innate immune responses to infection

“…For instance, in human and mouse cells, several alternatively spliced forms of genes involved in the TLR pathway have been shown to function as negative regulators of TLR signaling in order to prevent uncontrolled inflammation [9][10][11]. Additionally, several in-depth studies of individual genes suggest that alternative splicing plays an important role in increasing the diversity of transcripts encoding MHC molecules [12] and in modulating intracellular signaling and intercellular interactions through the expression of various isoforms of key cytokines [13,14], cytokine receptors [9,15,16], kinases [17] and adaptor proteins [18][19][20]. Yet, the extent to which changes in isoform usage are a hallmark of immune responses to infection remains largely unexplored at a genome-wide level [8,21].…”