Chemokines classes

Regrettably, the receptor classification system is much more complex than this. For example, the chemokine class of cytokine receptors is further subdivided into at least 16-20 different receptor subtypes, including CCRl, CCR2. .. CCRll, CXCRl, CXCR2. .. CXCR5. These receptors interact with more than 25-30 different types of chemokines. 

Szabo MC, Soo KS, Zlotnik A, Shall T. J Chemokine class differences in binding to the Duffy antigen-erythrocyte chemokine receptor. J Biol Chem 1995 270 25348-51. 

Chemokine receptors can bind multiple chemokines, and vice versa however the specificities are generally restricted by chemokine class (Table 1 and Table 2). 

The chemokines are a family of small (8-12kDa) secreted chemoattractant cytokines that share a common structure dictated by the pattern of disulfide bonds that form between conserved cysteine (C) residues. The number and spacing of cysteines in the amino-terminus defines four chemokine classes, CXC, CC, XC and CX3C, where X represents any amino acid (aa) except C (Baggiolini and Loetscher 2000). A majority of chemokines have two sets of disulfide bonds formed by the pairing the first two cysteines (Ci and C2) with two others in a C1-C3 and C2-C4 pattern. These secreted proteins bind to G protein-coupled heptahelical receptors found on leukocytes that are designated by the class of chemokine bound (CXCRs, CCRs, XCRs, and CX3CR, respectively) (Rossi and Zlotnik 2000). 

The activation of DRF-3 through the TREF dependent pathway allows for chemokines such as RANTES to be produced. It also leads to the production of DFN-a and EFN-(3, which are involved in anti-viral immunity. The TREF pathway, activated by either TLR-3 or TLR-4, can also induce MHC class-II expression and costimulatory molecules, thus leading to T-cell activation. This provides an important link between innate and adaptive immunity. 

Rostene W, Kitabgi P, Parsadaniantz SM (2007) Chemokines a new class of neuromodulator Nat Rev Neurosci 8 895-903... 

The first report of the action of a chemokine on neurons was published in 1993. The study demonstrated that IL-8 could increase the survival of cultured neurons (Araujo and Cotman, 1993). However, as can be appreciated from its name, IL-8 was not known to be a chemokine at that time and was instead classed as an interleukin. Indeed, the expression of chemokine receptors by neurons was not generally appreciated until around 1997/1998 when several reports suggested this. These reports included observations of the expression of chemokine receptors by neuronal cell lines (Hesselgesser et al. 1997), primary cultures of neurons (Meucci et al. 1998 Ohtani et al. 1998), and in brain sections from HlV-1, Alzheimer s disease, and other patients (Horuk et al. 1997 Westmoreland et al. 1998 Xia et al. 1997). Furthermore, data were obtained, suggesting functions for chemokine signaling in the development of the nervous system (Zou et al. 1998) as well as in neuronal survival and communication (Giovannelli et al. 1998 Meucci et al. 1998). 

Bazan JF, Bacon KB, Hardiman G et al (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385 640-644... 

Details regarding structural/functional differences among chemokines and their receptors are discussed elsewhere in this volume. Briefly, chemokines (and their cognate receptors) consist of four main classes (CC, CXC, CX3C and C) based on the number and spacing of at least four conserved cysteine residues (Murphy 2002). 

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