Cell-autonomous and non-cell-autonomous functions of caspase-8 Tehila Ben Moshe a , Tae-Bong Kang a , Andrew Kovalenko a , Hila Barash b,c , Rinat Abramovitch b,c , Eithan Galun b , David Wallach a, * a Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel b The Goldyne Savad Institute for Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel c MRI/MRS Laboratory, Human Biology Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel Abstract Cells in vivo do not act in isolation. Therefore, when attempting to predict the results of pharmaceutical modulation of the function of a protein, we must also take into account the non-cell-autonomous consequences of such modulation. Studies of caspase-8 initially indicated that it serves as the proximal enzyme in cellular self-destruction dictated through the extrinsic cell-death pathway. Later studies revealed that it also participates in mechanisms affecting cell growth and survival. This essay presents a brief account of a study indicating that, apart from functional changes that are cell autonomous, tissue-specific deletion of caspase-8 in mice also has non-cell-autonomous effects with consequences that might even be the opposite of the cell-autonomous ones. # 2008 Elsevier Ltd. All rights reserved. Keywords: Apoptosis; Caspase-8; Cell-autonomous; Therapy; TNF Since the day of destruction of the Holy Temple, prophecy was taken from the prophets and given to fools and babes. — Rabbi Johanan. Babylonian Talmud: Bava Batra 12b (3rd century CE) 1. On predicting the outcomes of pharmacological modulation of protein function This essay (which is based on a presentation delivered at the 11th International TNF Conference, May 2007) addresses two subjects that on first glance might appear unrelated namely, findings reached on analysis of various transgenic mouse models with mutants of caspase-8, and the limitations of our present ability to predict the usefulness of compounds affecting the function of a protein when they are applied to patients. Our attempts to apply to therapy the knowledge gained from molecular biology studies are based on our conviction that the following systematic stepwise progression should provide areliable notion of the potential clinical utility of a protein and of its inhibitors. We believe that (i) a thorough analysis of the molecular mechanisms in which the protein participates can provide clues as to the functions served by this protein in the cell; (ii) a comprehensive analysis of the way(s) in which modulation of the protein’s function affects cells in culture can teach us how such modulation affects the function of tissues in vivo and; (iii) that by carrying out such analyses in transgenic animal models we will be able to predict how drugs that affect the protein will act in patients. The TNF field has provided impressive illustrations of how useful the pharmaceutical modulation of cellular proteins can be. Anti-TNF agents (recombinant soluble TNF receptors and anti-TNF antibodies) have been successfully applied in more than a million patients to suppress harmful effects of chronic inflammatory conditions such as rheumatoid arthritis, the inflammatory bowel diseases, and psoriasis. Those remarkable achievements were the trigger for the current wave of attempts to apply inhibitors of many other cytokines to therapy. Research in the TNF field, however, has also provided dramatic illustrations showing that the systematic approach outlined above still falls short of allowing us to reliably predict the pharmaceutical utility of modulating a www.elsevier.com/locate/cytogfr Available online at www.sciencedirect.com Cytokine & Growth Factor Reviews 19 (2008) 209–217 Abbreviations: CY, cyclophosphamide; GdCl, gadolinium chloride; PHx, partial hepatectomy; KO, knockout; WT, wild-type. * Corresponding author. Tel.: +972 8 934 3941; fax: +972 8 934 3165. E-mail address: d.wallach@weizmann.ac.il (D. Wallach). 1359-6101/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.cytogfr.2008.04.012