Christophe Van Huffel

An Evolutionary and Functional Approach to the TNF Receptor/Ligand Family

Hormones undergo pronounced structural change in the course of evolution, yet each one retains its affinity for a specific receptor. Receptors also undergo change over time. How is it that structural changes in one member of a receptornigand pair are “anticipated” by changes in the structure of its partner? On an evolutionary scale, such changes may be very rapid. Hence, murine gamma interferon has but little affinity for the human gamma interferon receptor, and vice versu, although within each of these two species, the affinity between gamma interferon and its receptor has remained strong. Moreover, present-day functions of a given hormone may bear little semblance to the functions that its molecular ancestor served one billion years ago. How, then, were changes in function tolerated? The molecular cloning of several dozen proteins, somewhat arbitrarily lumped together as “interleukins,” “colony-stimulating factors,” “chemokines,” and “tumor necrosis factors” has permitted very detailed consideration of this issue. Not only the structure, but also the function of phylogenetically related molecules may be applied toward construction of a hypothesis as to how coevolution of hormones and their receptors may occur. Inasmuch as understanding of function is usually best advanced by analysis of the failure of function, much effort has been spent on the identification of defects of cytokine production or activity. Certain diseases can now be attributed to discrete mutations of genes encoding cytokines’” or their receptor^?^ and when nature has not provided such mutations, attempts have been made to introduce them artificially.6” As a result, the essential actions of cytokines have become somewhat clearer than they were a few years ago. In the present review, we offer a detailed description of the TNF ligand and receptor families and speculate as to their evolutionary and functional origins.