43 Pietro Ghezzi and Anthony Cerami (eds.), Tissue-Protective Cytokines: Methods and Protocols, Methods in Molecular Biology, vol. 982, DOI 10.1007/978-1-62703-308-4_3, © Springer Science+Business Media, LLC 2013 Chapter 3 Tissue-Protective Cytokines: Structure and Evolution Pietro Ghezzi and Darrell Conklin Abstract Cytokines are important mediators of host defense and immunity, and were first identified for their role in immunity to infections. It was then found that some of them are pathogenic mediators in inflammatory diseases and much of the emphasis is now on pro-inflammatory cytokines, also in consideration of the fact that TNF inhibitors became effective drugs in chronic inflammatory diseases. The recent studies on the tissue-protective activities of erythropoietin (EPO) led to the term “tissue-protective cytokine.” We dis- cuss here how tissue-protective actions might be common to other cytokines, particularly those of the 4-alpha helical structural superfamily. Key words Helical cytokines, Hematopoietic cytokines, 3D structure, Evolution, Host defense Surviving an infection is achieved in two ways: resistance (reducing the number of pathogens, such as by innate or adaptive immunity) and tolerance (surviving the damage produced by the pathogen), as outlined in Fig. 1. Read et al. (1) recently suggested that “dam- age control may be more important than pathogen control,” and the underlying mechanisms can probably be implicated in tissue damage non-necessarily associated with infections (2). Initially, cytokines were identified in an effort to characterize the effectors of “pathogen control,” with a focus on the antiviral and anticancer activity of the immune system (3). The idea was that these effector cytokines could be used as drugs. This led to the discovery of interferons, interleukins 1 and 2, and TNF. However the real impact in terms of “translational medicine” came from the discovery of the pro-inflammatory actions of TNF (4) and IL-1 (5), with the finding that cytokines produced by the immune system in response to infection can also cause inflammation and tissue damage. The enormous impact of this paradigm-shifting concept is demonstrated by the fact that TNF inhibitors (anti-TNF antibodies and soluble 1 Tissue-Protective Cytokines in the Context of Host Resistance