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Am. J. Respir. Cell Mol. Biol., Volume 27, Number 1, July, 2002 48-56

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

Michel P. Bihl, Karl Heinimann, Jochen J. Rüdiger, Oliver Eickelberg, André P. Perruchoud, Michael Tamm, and Michael Roth

Pulmonary Cell Research and Human Genetics, Department of Research, Zentrum für Lehre und Forschung, Kantonsspital Basel, Basel, Switzerland; and Department of Pathology, University Hospital Yale, Yale University, New Haven, Connecticut

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-6Delta 2), exon 4 (IL-6Delta 4), or missing both; and exons 2 and 4 (IL-6Delta 2,4). Only native IL-6 and IL-6Delta 4 encoded for proteins of ~ 26 and 17 kD, respectively. Although the overall structure and most functional sites of the IL-6Delta 4 protein were predicted to be maintained, IL-6Delta 4 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-6Delta 4 is likely to compete with native IL-6 for IL-6Ralpha binding but fails to transmit IL-6Rbeta -mediated signaling.


Abbreviations: interleukin, IL; nuclear factor, NF.




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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2002 American Thoracic Society.
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