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Publication Abstract from PubMed

Cytokines dimerize their receptors, with the binding of the 'second chain' triggering signaling. In the interleukin (IL)-4 and IL-13 system, different cell types express varying numbers of alternative second receptor chains (gammac or IL-13Ralpha1), forming functionally distinct type I or type II complexes. We manipulated the affinity and specificity of second chain recruitment by human IL-4. A type I receptor-selective IL-4 'superkine' with 3,700-fold higher affinity for gammac was three- to ten-fold more potent than wild-type IL-4. Conversely, a variant with high affinity for IL-13Ralpha1 more potently activated cells expressing the type II receptor and induced differentiation of dendritic cells from monocytes, implicating the type II receptor in this process. Superkines showed signaling advantages on cells with lower second chain numbers. Comparative transcriptional analysis reveals that the superkines induce largely redundant gene expression profiles. Variable second chain numbers can be exploited to redirect cytokines toward distinct cell subsets and elicit new actions, potentially improving the selectivity of cytokine therapy.

Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines.,Junttila IS, Creusot RJ, Moraga I, Bates DL, Wong MT, Alonso MN, Suhoski MM, Lupardus P, Meier-Schellersheim M, Engleman EG, Utz PJ, Fathman CG, Paul WE, Garcia KC Nat Chem Biol. 2012 Oct 28. doi: 10.1038/nchembio.1096. PMID:23103943^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.