CXC chemokines are members of the chemokine superfamily. The nomenclature is based on a conserved cysteine-containing amino acid sequence

at the amino terminus of each molecule: Ganetespib C, CC, CXC and CX3C, where X is an amino acid.35 Very little is known about the C and CX3C subsets of the CXC superfamily; they possibly mediate chemotaxis of precursor T cells and natural killer cells, respectively. The CC family has multiple ligands which serve as potent chemoattractants for monocytes. Based on the presence, or absence of a glutamic acid-leucine-arginine (ELR) amino acid motif at the amino terminus of each peptide, there are two subclasses of CXC chemokines.35,36 Those possessing the ELR motif bind to the receptors CXCR1 and CXCR2, while ELR-negative chemokines bind to CXCR3, CXCR4, CXCR5 and CXCR6. The ELR-positive CXC chemokines are relevant to liver injury as CXCR1 and CXCR2 are expressed on neutrophils, SECs and hepatocytes.37 During IR injury, special signals entice neutrophils to extravasate to the hepatic parenchyma. ELR containing CXC chemokines such as macrophage inflammatory protein-2 (MIP-2), IL-8, cytokine-induced neutrophil chemoattractant

(CINC)-1 are potent chemoattractants for neutrophils.23,25,38–40 Over-expression of CXC chemokines in hepatocytes PLK inhibitor lead to a swift infiltrative response by neutrophils, which then execute inflammation and injury.38,39 In contrast, neutralizing antibodies against CXC chemokines, or CXC antagonists attenuate accumulation of neutrophils and liver injury during IR.38–40 Pro-forms of CXC chemokines bound to extracellular matrix in the liver can also provide a chemotactic gradient for neutrophils following their cleavage in response to IR.25 It is important to note that CXC chemokines do not always function as chemoattractants and

are Chlormezanone therefore, not irrevocably “bad.” Colleti et al. has previously reported hepatocyte proliferation in response to increasing concentrations of ERL-positive chemokines.41 Also, expression levels of CXC chemokines have been described to increase following 70% partial hepatectomy (PH); when these specific CXC chemokines were inhibited by neutralizing antibodies, liver regeneration was impaired with a significant reduction in the mass of remnant liver.42 Conversely, treatment of mice with MIP-2 accelerated hepatocyte proliferation and liver regeneration after PH.42 Moreover, genetic deletion or pharmacological antagonism of CXCR2 after hepatic IR augmented hepatocyte proliferation, and reduced injury. While the precise mechanisms underlying the pleiotropic roles of CXC chemokines after PH and in liver IR injury models are unclear, it is postulated that their divergent effects may relate to the concentration of chemokines produced in response to these specific insults.