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IL‐8 single‐chain homodimers and heterodimers: Interactions with the chemokine receptors CXCR1, CXCR2, and DARC

Covalent single‐chain dimers of the chemokine interleukin‐8 (IL‐8) have been designed to mimic the dimeric form of IL‐8 in solution and facilitate the production of heterodimer variants of IL‐8. Physical studies indicated that use of a simple peptide linker to join two subunits, while allowing receptor binding and activation, led to self‐association of the tethered dimers. However, addition of a single disulfide crosslink between the tethered subunits prevented this multimer from forming, yielding a species of dimer molecular weight. Crosslinked single‐chain dimers bind to both IL‐8 neutrophil receptors CXCR1 and CXCR2 as well as to DARC, as does a double disulfide‐linked dimer with no peptide linker. In addition, neutrophil response to these dimers as measured by chemotaxis or /‐glucuronidase release is similar to that elicited by wild‐type IL‐8, providing evidence that the dissociation of the dimeric species is not required for these biologically relevant activities. Finally, through construction of single‐chain heterodimer mutants, we show that only the first subunit's ELR motif is functional in the single‐chain variants.