title: Lipopolysaccharide-enhanced transcellular transport of HIV-1 across the blood-brain barrier is mediated by luminal microvessel IL-6 and GM-CSF.
abstract: 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.
authors: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors: Shinya
authors: S
authors: Dohgu
authors: Melissa A
authors: MA
authors: Fleegal-DeMotta
authors: William A
authors: WA
authors: Banks
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016764:Cell Polarity; D002478:Cells, Cultured; D062507:Claudin-5; D057167:Claudins / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D057900:Transcytosis / Q000187:drug effects*; D062826:Zonula Occludens-1 Protein
chemical_list: D000906:Antibodies; D062507:Claudin-5; D057167:Claudins; C491511:Cldn5 protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases