title: 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.
authors.affiliation: Pulmonary Cell Research and Human Genetics, Department of Research, Zentrum für Lehre und Forschung, Kantonsspital Basel, Switzerland. michel.bihl@unibas.ch
authors.forename: Michel P
authors.initials: MP
authors.lastname: Bihl
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.forename: Jochen J
authors.initials: JJ
authors.lastname: Rüdiger
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: André P
authors.initials: AP
authors.lastname: Perruchoud
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D017398:Alternative Splicing; D001665:Binding Sites; D002478:Cells, Cultured; D019281:Dimerization; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008958:Models, Molecular; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D019947:Receptors, Interleukin-6 / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D020033:Protein Isoforms; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6