CXCL1/CXCL8 (GROα/IL-8) in human diabetic ketoacidosis plasma facilitates leukocyte recruitment to cerebrovascular endothelium in vitro

Am J Physiol Endocrinol Metab. 2014 May 1;306(9):E1077-84. doi: 10.1152/ajpendo.00659.2013. Epub 2014 Mar 11.


Diabetic ketoacidosis (DKA) in children is associated with intracranial vascular complications, possibly due to leukocyte-endothelial interactions. Our aim was to determine whether DKA-induced inflammation promoted leukocyte adhesion to activated human cerebrovascular endothelium. Plasma was obtained from children with type 1 diabetes either in acute DKA or in an insulin-controlled state (CON). Plasma concentrations of 21 inflammatory analytes were compared between groups. DKA was associated with altered circulating levels of ↑CXCL1 (GROα), ↑CXCL8 (IL-8), ↑IL-6, ↑IFNα2, and ↓CXCL10 (IP-10) compared with CON. These plasma analyte measurements were then used to create physiologically relevant cytokine mixtures (CM). Human cerebral microvascular endothelial cells (hCMEC/D3) were stimulated with either plasma (DKA-P or CON-P) or CM (DKA-CM or CON-CM) and assessed for polymorphonuclear leukocyte (PMN) adhesion. Stimulation of hCMEC/D3 with DKA-P or DKA-CM increased PMN adhesion to hCMEC/D3 under "flow" conditions. PMN adhesion to hCMEC/D3 was suppressed with neutralizing antibodies to CXCL1/CXCL8 or their hCMEC/D3 receptors CXCR1/CXCR2. DKA-P, but not DKA-CM, initiated oxidative stress in hCMEC/D3. Expression of ICAM-1, VCAM-1, and E-selectin were unaltered on hCMEC/D3 by either DKA-P or DKA-CM. In summary, DKA elicits inflammation in children associated with changes in circulating cytokines/chemokines. Increased CXCL1/CXCL8 instigated PMN adhesion to hCMEC/D3, possibly contributing to DKA-associated intracranial vascular complications.

Keywords: CXC chemokine ligand; brain; cell trafficking; chemokines; diabetes; growth-regulated oncogene-α; human; inflammation; ketoacidosis; neutrophils; pediatric.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / blood supply*
  • Brain / immunology
  • Case-Control Studies
  • Cells, Cultured
  • Chemokine CXCL1 / blood*
  • Chemokine CXCL1 / pharmacology
  • Chemotaxis, Leukocyte* / drug effects
  • Child
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / complications
  • Diabetic Ketoacidosis / blood*
  • Diabetic Ketoacidosis / immunology
  • Electric Impedance
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology*
  • Female
  • Humans
  • Interleukin-8 / blood*
  • Interleukin-8 / pharmacology
  • Male


  • CXCL1 protein, human
  • CXCL8 protein, human
  • Chemokine CXCL1
  • Interleukin-8