Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120.
BACKGROUND
The blood brain barrier (BBB) is the first line of defence of the central nervous system (CNS) against circulating pathogens, such as HIV. The cytotoxic HIV protein, gp120, damages endothelial cells of the BBB, thereby compromising its integrity, which may lead to migration of HIV-infected cells into the brain. Fibroblast growth factor 2 (FGF2), produced primarily by astrocytes, promotes endothelial cell fitness and angiogenesis. We hypothesized that treatment of human umbilical vein endothelial cells (HUVEC) with FGF2 would protect the cells from gp120-mediated toxicity via endothelial cell survival signalling.


RESULTS
Exposure of HUVEC to gp120 resulted in dose- and time-dependent cell death; whereas, pre-treatment of endothelial cells with FGF2 protected cells from gp120 angiotoxicity. Treatment of HUVEC with FGF2 resulted in dose- and time-dependent activation of the extracellular regulated kinase (ERK), with moderate effects on phosphoinositol 3 kinase (PI3K) and protein kinase B (PKB), also known as AKT, but no effects on glycogen synthase kinase 3 (GSK3beta) activity. Using pharmacological approaches, gene transfer and kinase activity assays, we show that FGF2-mediated angioprotection against gp120 toxicity is regulated by crosstalk among the ERK, PI3K-AKT and PKC signalling pathways.


CONCLUSIONS
Taken together, these results suggest that FGF2 may play a significant role in maintaining the integrity of the BBB during the progress of HIV associated cerebral endothelial cell damage.
Langford
Dianne
D
Department of Pathology, University of California, San Diego, La Jolla, CA, USA. tdlangford@ucsd.edu
Hurford
Rosemary
R
Hashimoto
Makoto
M
Digicaylioglu
Murat
M
Masliah
Eliezer
E
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1; D006801:Humans; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D015699:HIV Envelope Protein gp120; D016222:Fibroblast Growth Factor 2