Mouse IL-12 acts on both mouse and human cells; human IL-12 acts only on human cells. This species specificity is determined by the p35 subunit of the IL-12 heterodimer. Since mouse and human p35 sequences are 60% identical, the determinants for the species specificity most likely reside in the nonhomologous sequences of mouse p35. To identify the regions on the p35 subunit interacting with the mouse IL-12 receptor, we constructed a series of chimeric mouse-human p35 molecules by replacing mouse sequences with the nonhomologous human counterparts. An IL-12 heterodimer containing a mouse-human p35 chimera with five residues changed in three discontinuous sites had drastically reduced (750-3000-fold) bioactivities on mouse cells. However, the competitive binding activity of the same mutant IL-12 heterodimer on mouse cells was only reduced 30-fold relative to wild-type IL-12. These findings therefore suggest that 1) the mouse p35 subunit participates in both receptor binding and signaling, 2) the mutations introduced into p35 affect signaling to a much greater extent than receptor binding, and 3) the five residues identified on p35 are required for interacting with the mouse, but not with the human IL-12 receptor and as such contribute extensively to the observed species specificity of IL-12.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				I. Shiratori, M. Matsumoto, S. Tsuji, M. Nomura, K. Toyoshima, and T. Seya Molecular cloning and functional characterization of guinea pig IL-12 Int. Immunol., September 1, 2001; 13(9): 1129 - 1139. [Abstract] [Full Text] [PDF]

				D. H. Presky, L. J. Minetti, S. Gillessen, V. L. Wilkinson, C.-Y. Wu, U. Gubler, R. Chizzonite, and M. K. Gately Analysis of the Multiple Interactions Between IL-12 and the High Affinity IL-12 Receptor Complex J. Immunol., March 1, 1998; 160(5): 2174 - 2179. [Abstract] [Full Text] [PDF]

				J. Zou, D. H. Presky, C.-Y. Wu, and U. Gubler Differential Associations between the Cytoplasmic Regions of the Interleukin-12 Receptor Subunits beta 1 and beta 2 and JAK Kinases J. Biol. Chem., February 28, 1997; 272(9): 6073 - 6077. [Abstract] [Full Text] [PDF]