Cytokine and Cytokine Receptor Pleiotropy and Redundancy*

Cytokines represent a diverse group of molecules that collectively exert a wide range of actions (1). The term cytokine is rather general, technically referring to a molecule made by one cell that acts on another, but cytokines are primarily growth factors and hormones of the immune and hematopoietic systems. The term broadly encompasses many of the interleukins and colony-stimulating factors (which are also referred to as type I cytokines) and interferons (which sometimes are referred to as type II cytokines) (1). Certain molecules, such as erythropoietin, thrombopoietin, growth hormone, and prolactin, although not classically thought of as typical cytokines, have similar structures and signaling mechanisms to type I cytokines (1). Many individual cytokines are themselves pleiotropic, exerting multiple actions, and particularly in vitro, many cytokines have overlapping actions (2, 3). There are multiple different possible mechanisms that can explain pleiotropic and overlapping actions for different cytokines. Pleiotropic actions can be explained by the presence of receptors for a cytokine on multiple lineages or by a cytokine having the ability to activate multiple signaling pathways wherein different signaling pathways differentially contribute to different functions. Overlapping actions by different cytokines can be explained by similar cellular distributions of specific receptors for different cytokines as well as by the sharing of signaling pathways, which particularly occurs when different receptors share similar motifs that mediate the coupling to the same pathways. In addition, however, cytokine pleiotropy and redundancy can be at least partially explained, respectively, by the ability of certain cytokines to signal via more than one type of receptor complex and by the sharing of an individual receptor component by more than one cytokine. We will herein summarize a range of different systems wherein cytokine receptor components are shared, discussing the implications thereof. For type I cytokines, these include the sharing of the common chain, c, by interleukin-3 (IL-3), 1 IL-5, and granulocytemacrophage colony-stimulating factor (GM-CSF); the sharing of gp130 by IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), novel neurotrophin1/B cell-stimulating factor-3/cardiotrophin-like cytokine (NNT-1/ BSF-3/CLC), and cardiotrophin-1 (CT-1); the sharing of LIFR by LIF, OSM, CNTF, NNT-1/BSF-3/CLC, and CT-1; the sharing of CNTFR by CNTF and NNT-1/BSF-3/CLC; the sharing of IL12R 1 by IL-12 and IL-23; the sharing of c by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21; the sharing of IL-2R by IL-2 and IL-15; the sharing of IL-4R and IL-13R 1 by IL-4 and IL-13; and the sharing of IL-7R by IL-7 and thymic stromal lymphopoietin (TSLP) (Table I). The cytokines that can signal via more than one complex include IL-2, IL-4, human OSM, and murine IL-3. For type II cytokines, we discuss the sharing of IL-10R by IL-10 and IL-22, the sharing of IL20R and IL-20R by IL-19, IL-20, and IL-24, and the sharing of IL-22R by IL-20, IL-22, and IL-24.