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. 2012 Feb;35(1):130-7.
doi: 10.1007/s10753-011-9297-5.

Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation

Hongkuan Fan  1 , Donald Wong, Sarah H Ashton, Keith T Borg, Perry V Halushka, James A Cook
Affiliations

Beneficial effect of a CXCR4 agonist in murine models of systemic inflammation

Hongkuan Fan et al. Inflammation. 2012 Feb.

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.

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Figures

Fig. 1
Fig. 1
Structures of SDF-1α and CTCE-0214.
Fig. 2
Fig. 2
Effect of CTCE-0214 on LPS-induced plasma TNF-α, IL-6, and IL-10 production. CD-1 mice were injected with LPS (25 mg/kg, i.p.) with/without CTCE-0214 (1, 10, or 25 mg/kg, i.v.). One hour after the injections, the mice were killed and plasma TNF-α (a), IL-6 (b), and IL-10 (c) were determined by ELISA. *p<0.05 compared with control; #p<0.05 compared with LPS stimulation. N=3–5.
Fig. 3
Fig. 3
Effect of CTCE-0214 on zymosan-induced plasma TNF-α, IL-6, and IL-10 production. CD-1 mice were injected with zymosan (500 mg/kg, i.p.). One and three hours after zymosan injection, mice were injected with CTCE-0214 (25 mg/kg, i.v.). Six hours after zymosan injection, mice were injected with CTCE-0214 (25 mg/kg, i.p.). Twenty-four hours after zymosan challenge, mice were killed and plasma TNF-α (a), IL-6 (b), and IL-10 (c) were measured by ELISA. *p<0.05 compared with control; #p<0.05 compared with zymosan stimulation. N=3–6.
Fig. 4
Fig. 4
Effect of CTCE-0214 on severe CLP-induced sequelae. CD-1 mice were subjected to CLP in the absence of antibiotics. CTCE-0214 (25 mg/kg) or vehicle PBS was administrated by injection subcutaneously at 2, 18, 26, 42 and 50 h after CLP. Mortality was monitored every 12 h until 120 h (a). N=15/group. Statistics were determined with the log-rank (Mantel–Cox) test using GraphPad Prism software. *p<0.05 compared with the PBS group. CTCE-0214 (10 mg/kg) or vehicle PBS was also administrated by injection subcutaneously at 2 and 6 h after CLP. Plasma TNF-α (b), IL-6 (c), and IL-10 (d) were measured 24-h post-CLP. *p<0.05 compared with control, #p<0.05 compared with the PBS group. N=3–5.
Fig. 5
Fig. 5
CLP-induced plasma IL-6 and SDF-1α production. CD-1 mice were subjected to moderate sepsis model (CLP X1) or severe sepsis model (CLP X2). Twenty-four hours after CLP, mice were killed and whole blood was collected. Plasma levels of IL-6 (a) and SDF-1α (b) were measured by ELISA. *p<0.05 compared with sham control; #p<0.05 compared with moderate CLP. N=3.
Fig. 6
Fig. 6
Effect of CTCE-0214 on LPS-induced IL-6 production in BMDM. BMDMs from CD-1 mice were incubated with CTCE-0214 (28–280nM) for 1 h followed by activation with LPS (100 ng/ml, Sigma) for 18 h. LPS-induced IL-6 production was examined by ELISA. *p<0.05 compared with basal control; #p<0.05 compared with LPS stimulation. N=3.
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