26 Three-dimensional structure studies have shown that many otherwise nonhomologous cytokines adopt similar conformations. These structural features of some cytokines permit their grouping into families. Members of the large IL-2/IL-4 family (including IL-2 to IL-7, IL-9, IL-11, IL-12 p35, IL-13, IL-15, type I and type II IFNs, and CSFs) share a common tertiary architecture characterized by bundles of four antiparallel α-helices in a spatially similar arrangement.26-28 Two

important cytokine families show distinct structures: The IL-1 family, consisting of IL-1α, IL-1β, Inhibitors,research,lifescience,medical IL-1 receptor antagonist (IL-1ra), and IL-18, is characterized by a β-trefoil structure.26 IL-1α and IL-1β exert identical actions via binding to a single 80-kDa cell surface receptor (IL-1RI) and an accessory protein (AcP).29 IL-1β and IL-18 are formed as biologically inactive precursors that are cleaved by the enzyme Inhibitors,research,lifescience,medical ICE (caspase 1).30 IL-1ra is a highly specific, competitive antagonist of IL-1RI, blocking

all actions of IL-1 by inhibiting the association between IL-1RI and AcP30 Four other Inhibitors,research,lifescience,medical members of this family have recently been identified, but their biological activity – especially with regard to their actions on the CNS – remains to be elucidated.31 Another structurally similar cytokine family is that of the TNFs including TNF-α, TNF-β, LT-β, Fas EVP4593 ligand (CD90L), CD40 ligand, TNF-related apoptosis-inducing ligand (TRAIL), and several other TNF ligand superf amily members.32 The characteristic structure of this family is a β-jellyroll26 Members of the TNF family act as trimers, most of which are membrane-bound and so are quite distinct in their properties from the other cytokines.33 Clustered chromosomal localization of

cytokines Inhibitors,research,lifescience,medical The cytokines are not members of a single gene superfamily. Remarkably few similarities have been Inhibitors,research,lifescience,medical noted in their primary nucleotide or amino acid sequences, and their genes are, for the most part, scattered throughout the genome. However, some chromosomal regions where cytokine coding genes are clustered are known. Most interestingly, some of these chromosomal regions seem to be associated with psychiatric disorders, especially schizophrenia. from Chromosome 1 One cluster of genes coding for members of the IL-10 family is located on chromosomal regions 1q32. These are the cytokines IL-10, IL-19, IL-20, and IL-24.34 This region is of major interest in genetic schizophrenia research, as several linkage studies identified a susceptibility locus for schizophrenia there.35-37 Indeed, a recent study points to the IL-10 gene itself as a susceptibility gene for schizophrenia.38 Chromosome 2 With exception of IL-18, the members of the IL-1 family are encoded by closely linked genes on the long arm of chromosome 2.31 An association of polymorphisms in the genes coding for IL-1α, IL-1β, and IL-1ra with schizophrenia was reported by Katila and colleagues.