Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF

Elevated levels of cytokines/chemokines contribute to increased neuroinvasion of human immunodeficiency virus type 1 (hiv-1). previous work showed that lipopolysaccharide (lps),which is present in the plasma of patients with hiv-1,enhanced transcellular transport of hiv-1 across the blood-brain barrier (bbb) through the activation of p38 mitogen-activated protein kinase (mapk) signaling in brain microvascular endothelial cells (bmecs). here,we found that lps (100 μg/ml,4 hr) selectively increased interleukin (il)-6 and granulocyte-macrophage colony-stimulating factor (gm-csf) release from bmecs. the enhancement of hiv-1 transport induced by luminal lps was neutralized by treatment with luminal,but not with abluminal,antibodies to il-6 and gm-csf without affecting paracellular permeability as measured by transendothelial electrical resistance (teer). luminal,but not abluminal,il-6 or gm-csf also increased hiv-1 transport. u0126 (mapk kinase (mek)1/2 inhibitor) and sb203580 (p38 mapk inhibitor) decreased the lps-enhanced release of il-6 and gm-csf. these results show that p44/42 and p38 mapk signaling pathways mediate the lps-enhanced release of il-6 and gm-csf. these cytokines,in turn,act at the luminal surface of the bmec to enhance the transcellular transport of hiv-1 independently of actions on paracellular permeability. © 2011 dohgu et al; licensee biomed central ltd.