title: Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation.
abstract: The chemokine CXC receptor 4 (CXCR4) is activated by stromal cell-derived factor (SDF-1α). CXCR4 may be part of a lipopolysaccharide (LPS) sensing co-clustering complex that modulates TLR4 activation and evidence suggest that SDF-1α can activate anti-inflammatory signaling pathways and suppress inflammation. In the present study we examined the hypothesis that the SDF-1α peptide analog and CXCR4 agonist CTCE-0214 is anti-inflammatory in three distinct models of murine systemic inflammation. Our findings demonstrate that CTCE-0214 in vivo significantly suppressed plasma tumor necrosis factor alpha (TNF-α) increases in acute endotoxemia and following zymosan-induced multiple organ dysfunction syndrome (MODS). In both models, CTCE-0214 did not suppress plasma increases in the anti-inflammatory cytokine interleukin (IL)-10. CTCE-0214 improved survival without antibiotics in a model of severe sepsis induced by cecal ligation and puncture (CLP). CTCE-0214 also decreased plasma increases in IL-6 but not TNF-α and IL-10 in response to CLP-induced inflammation. We demonstrated in a moderately severe model of CLP (one puncture) that IL-6 levels at 24 h were similar to sham controls. However in severe CLP (two punctures) plasma IL-6 levels were markedly elevated. Plasma SDF-1α levels varied inversely with the plasma IL-6. In addition to the beneficial effect of CTCE-0214 in these models of systemic inflammation in vivo, we also demonstrated that the analog dose dependently suppressed LPS-induced IL-6 production in bone marrow-derived macrophages. CTCE-0214 therefore may be beneficial in controlling inflammation sepsis and systemic inflammatory syndromes.
authors.affiliation: Department of Neuroscience, The Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA. fanhong@musc.edu
authors.forename: Hongkuan
authors.initials: H
authors.lastname: Fan
authors.forename: Donald
authors.initials: D
authors.lastname: Wong
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Ashton
authors.forename: Keith T
authors.initials: KT
authors.lastname: Borg
authors.forename: Perry V
authors.initials: PV
authors.lastname: Halushka
authors.forename: James A
authors.initials: JA
authors.lastname: Cook
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000188:drug therapy*; D019718:Receptors, CXCR4 / Q000819:agonists* / Q000276:immunology*; D018805:Sepsis / Q000188:drug therapy; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015054:Zymosan
chemical_list: C573959:CTCE-0214; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015054:Zymosan