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A Spliced Isoform of Interleukin 6 mRNA Produced by Renal Cell Carcinoma Encodes for an Interleukin 6 Inhibitor

¹ Equipe Cytokine et Cancer, Unité Institut National de la Sante et de la Recherche Medicale, Centre Léon Bérard, Lyon, France, and ² Hôpital Edouard Herriot, Place d'Arsonval, Lyon, France

Requests for reprints: Dr. J.Y. Blay, Equipe Cytokine et Cancer, Unité Institut National de la Sante et de la Recherche Medicale, 590 Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France. Phone: 33-47878-2828; Fax: 33-47878-2716; E-mail: blay{at}lyon.fnclcc.fr.

Interleukin 6 (IL-6) is a multifunctional and pleiotropic cytokine and in renal cell carinoma (RCC), this cytokine exerts proinflammatory, immunosuppressive and growth stimulating properties. A spliced isoform of IL-6 mRNA has been described in peripheral blood mononuclear cells and encodes for a potential protein lacking IL-6 activity. In the present study, a novel spliced form of IL-6 mRNA was found detectable in RCC cell lines, normal renal cells, but not in other tumor cells. This splicing resulted in a frameshift and the generation of multiple stop codon in the spliced IL-6 mRNA. However, two ATG of the third IL-6 exon were identified as translation initiation sites and two truncated IL-6 (tIL-6) with the expected molecular weight were recovered from transfected cell supernatant. The cDNA of a spliced form of IL-6 mRNA detected in RCC lines was cloned, and expressed in a baculovirus expression vector. The functional properties of the tIL-6 were investigated and this protein blocked IL-6 bioactivity, including mitogenic activity on tumor cells. In conclusion, this spliced form of IL-6 mRNA detected in RCC encodes for a truncated IL-6 with IL-6 antagonist properties.

Key Words: RCC • IL-6 • alternative spacing