Cytokines are key messenger molecules in cell-to-cell communication and are involved in various aspects of the immune system such as maintaining homeostasis and mediating and resolving pathologic conditions. Interleukin 17 (IL-17) family is a recently identified group of cytokines sharing homology in amino acid sequences with highly conserved cysteine residues critical to their 3-dimensional shape [1
]. So far, six members, IL-17A (commonly refer to IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25) and IL-17F, have been identified [2
IL-17A is a founding member of the IL-17 family and serves as an essential player in host defense during infection while aberrant expression of IL-17A is associated with many autoimmune diseases and cancer [6
]. IL-17A is a pleiotropic cytokine that acts on multiple cell types to enhance the production of proinflammatory molecules. Expression of IL-17A, therefore, is tightly regulated. A subset of CD4+ T cells, Th17, and innate immune cells such as γδ T cells are major producers of IL-17A although other subsets have been identified [9
IL-17F, sharing the strongest amino acid sequence with IL-17A, resembles IL-17A in the cellular sources and regulation [14
]. It was thought to play a redundant role with IL-17A since IL-17F also regulates proinflammatory gene expression in vitro
. Yet, IL-17F exhibits a distinctive role, for instance, during allergic inflammation in lung and intestinal inflammation in vivo [15
]. IL-17A and IL-17F proteins can form a heterodimer and behave in a similar fashion to the homodimeric forms of IL-17A and IL-17F in vitro
IL-25, most distant from IL-17A in IL-17 family, promotes Th2 cell-mediated immune responses, thereby contributing to allergic disease and defense against helminthic parasites [20
]. Diverse cellular sources have been linked to the expression of IL-25 such as epithelial cells, eosinophils, mast cells, and basophils. Three remaining cytokines in the IL-17 family, IL-17B, IL-17C and IL-17D, currently are poorly studied with regards to their biological function and receptors.
IL-17R family is comprised of 5 members (IL-17RA, RB, RC, RD and RE). All of them share sequence homology to the earliest identified member, IL-17RA. So far, the biological roles or ligands of IL-17RD or IL-17RE are not clear. Although the expression and roles of IL-17RA have been known for some time, the recent evidence points to a much broader role of IL-17RA in signaling by IL-17A, IL-17F and IL-25.
In this review, we describe the current understanding on the receptor organization, signaling mechanisms as well as function of IL-17A, IL-17F and IL-25.