A large family of cytokines are produced by various cells of the body, and the cytokine superfamily includes interleukins, chemokines, colony-stimulating factors (CSF), interferons, and the transforming growth factors (TNF) and tumor necrosis factor (TGF) familes. Cytokines exist in broad families that are structurally related but may contain rather diverse cytokine functions.
Families of cytokines share sequence similarity and exhibit homology and some promiscuity in their reciprocal receptor systems. They do not exhibit functional similarity. Cytokine families also contain important regulatory cell membrane receptor-ligand pairs, refl ecting evolutionary pressures that use common structural motifs in diverse immune functions in higher mammals. The TNF/TNF receptor superfamily contains immunoregulatory cytokines, including TNF- α ; lymphotoxins; and cellular ligands, such as CD40L, which mediates B cell and T cell activation, and FasL (CD95), which promotes apoptosis.
Similarly, the IL-1/IL-1 receptor superfamily contains cytokines, including IL-1 β , IL-1 α , IL-receptor antagonist, IL-18, and IL-33, which mediate physiologic and host-defense function, but this family also includes the Toll-like receptors, a series of mammalian pattern-recognition molecules with a crucial role in recognition of microbial species early in innate responses.
Cytokine receptors exist in structurally related families and comprise high-affinity molecular signaling complexes that facilitate cytokine-mediated communication.
Type I cytokine receptors have certain conserved motifs in their extracellular amino-acid domain, and lack an intrinsic protein tyrosine kinase activity. This family includes receptors for IL2 (beta-subunit), IL3, IL4, IL5, IL6, IL7, IL9, IL11, IL12, GM-CSF, G-CSF, Epo, LIF, CNTF, and also the receptors for Thrombopoietin (TPO), Prolactin, and Growth hormone. Type I cytokine receptor family is subdivided into three subsets on the basis of the ability of family members to form complexes with one of three different types of receptor signaling components (gp130, common beta, and common gamma - the gamma-chain of the IL2 receptor).
Type II cytokine receptors are multimeric receptors composed of heterologous subunits, and are receptors mainly for interferons. This family includes receptors for IFN-alpha, IFN-beta, IFN-gamma, IL10, IL22, and tissue factor. The extracellular domains of type II cytokine receptors share structural similarities in their ligand-binding domain. Several conserved intracellular sequence motifs have been described, which probably function as binding sites for the intracellular effector proteins JAK and STAT proteins.
Chemokine receptors are G protein-coupled receptors with 7 transmembrane structure and couple to G-protein for signal transduction. Chemokine receptors are divided into different families: CC chemokine receptors, CXC chemokine receptors, CX3C chemokine receptors, and XC chemokine receptor (XCR1).
Tumor necrosis factor receptor (TNFR) family members share a cysteine-rich domain (CRD) formed of three disulfide bonds surrounding a core motif of CXXCXXC creating an elongated molecule. TNFR is associated with procaspases through adapter proteins (FADD, TRADD, etc.) that can cleave other inactive procaspases and trigger the caspase cascade, irreversibly committing the cell to apoptosis.
TGF-beta receptors are single pass serine/threonine kinase receptors. TGF-beta receptors include TGFBR1, TGFBR2, and TGFBR3 which can be distinguished by their structural and functional properties.