Changing the chemokine gradient: CINC1 crosses the blood-brain barrier.
Chemokines are a large family of small, inducible, secreted, chemoattractant cytokines that are involved in inflammatory processes. It is well known that systemic and CNS infections cause disruption of the blood-brain barrier (BBB); however, it is not clear how chemokines are involved in this process. We studied the pharmacokinetics of the passage of the chemokine cytokine-induced neutrophil chemoattractant-1 (CINC1) from blood to brain after i.v. bolus injection and its efflux out of the brain after i.c.v. injection. Radiolabeled CINC1 was injected i.v. into mice, and the results were determined by multiple-time regression analysis. Using HPLC, we detected intact CINC1 in brain homogenate and blood after i.v. administration. CINC1 accumulated in the cerebral vasculature but also crossed the BBB completely and rapidly. No saturation of the influx was found, suggesting that either CINC1 crossed the BBB by simple diffusion or the dynamic interactions of binding and internalization precluded the self-inhibition typical of a transport system. Furthermore, there was no efflux system, with CINC1 exiting the brain at the same rate as reabsorption of CSF. The CINC1 injected into blood or CSF did not cause any breakdown of the BBB during the course of the experiments. Thus, the influx of CINC1 may alter the "chemokine gradient" across the BBB and therefore affect inflammatory reactions involving the CNS.
Department of Medicine, Tulane University School of Medicine and the VA Medical Center, New Orleans, LA 70112, USA. wpan@tulane.edu
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D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000502:physiology*; D002196:Capillaries / Q000737:chemistry / Q000378:metabolism; D002469:Cell Separation; D002540:Cerebral Cortex / Q000098:blood supply / Q000737:chemistry / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D002630:Chemotactic Factors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D006133:Growth Substances / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D051379:Mice; D013668:Technetium Tc 99m Aggregated Albumin / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution
D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D013668:Technetium Tc 99m Aggregated Albumin