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Faithful Expression of the Human 5q31 Cytokine Cluster in Transgenic Mice¹

Dee A. Lacy^*, Zhi-En Wang^*, Derek J. Symula, Clifford J. McArthur^*, Edward M. Rubin, Kelly A. Frazer and Richard M. Locksley^2,*

^* Howard Hughes Medical Institute and Departments of Medicine and Microbiology/Immunology, University of California, San Francisco, CA 94143; and Genome Science Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720

Interleukins -4, -5, and -13, cardinal cytokines produced by Th2 cells, are coordinately expressed and clustered in 150-kb syntenic regions on mouse chromosome 11 and human chromosome 5q31. We analyzed two sets of human yeast artificial chromosome transgenic mice that contained the 5q31 cytokines to assess whether conserved sequences required for their coordinate and cell-specific regulation are contained within the cytokine cluster itself. Human IL-4, IL-13, and IL-5 were expressed under Th2, but not Th1, conditions in vitro. Each of these cytokines was produced during infection with Nippostrongylus brasiliensis, a Th2-inducing stimulus, and human IL-4 was generated after activation of NK T cells in vivo. Consistently fewer cells produced the endogenous mouse cytokines in transgenic than in control mice, suggesting competition for stable expression between the mouse and human genes. These data imply the existence of both conserved trans-activating factors and cis-regulatory elements that underlie the coordinate expression and lineage specificity of the type 2 cytokine genes in lymphocytes.

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