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Bypassing Inflammatory Signaling

Tumor necrosis factor (TNF) binds to TNF receptors and stimulates inflammatory responses. In patients, an elevated level of TNF is associated with diseases such as rheumatoid arthritis, and inhibition of TNF signaling can be used to treat these diseases. Steed et al. describe an approach that prevents TNF signaling. They used structure-based protein design to engineer dominant-negative TNFs that form heterotrimers with native TNF and in turn prevent binding to TNF receptors. Experiments in animal models show that this approach has promise in attenuating TNF-mediated pathology in vivo. P. M. Steed, M. G. Tansey, J. Zalevsky, E. A. Zhukovsky, J. R. Desjarlais, D. E. Szymkowski, C. Abbott, D. Carmichael, C. Chan, L. Cherry, P. Cheung, A. J. Chirino, H. H. Chung, S. K. Doberstein, A. Eivazi, A. V. Filikov, S. X. Gao, R. S. Hubert, M. Hwang, L. Hyun, S. Kashi, A. Kim, E. Kim, J. Kung, S. P. Martinez, U. S. Muchhal, D.-H. T. Nguyen, C. O'Brien, D. O'Keefe, K. Singer, O. Vafa, J. Vielmetter, S. C. Yoder, B. I. Dahiyat, Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science 301, 1895-1898 (2003). [Abstract] [Full Text]