HIV envelope protein gp120-triggered CD4+ T-cell adhesion to vascular endothelium is regulated via CD4 and CXCR4 receptors.
Activation of T-lymphocytes is an important component of inflammatory and infectious processes, including HIV infection. It is regulated via the actions of various cell-surface receptors, including CD4 and CXCR4. We examined the roles of CD4 and CXCR4 in the adhesive interaction of CD4+T-cells with the vascular endothelium. CD4+Jurkat cells were incubated in the presence or absence of anti-CD4 to stimulate CD4, or with SDF-1 alpha, a cognate ligand of CXCR4. Stimulation of CD4 or CXCR4 each significantly enhanced cell adhesion. We next stimulated the two receptors together, using gp120, a component of HIV. This enhanced cell adhesion was greater than stimulation of CD4 or CXCR4 individually. Western blotting revealed that stimulation of CXCR4 by SDF-1 alpha significantly increased the phosphorylation of ERK1/2 in Jurkat cells. Treatment with anti-CD4 also activated ERK1/2, although to a lesser extent. When the expression of CD4 was reduced by siRNA transfection, both CD4-dependent adhesion and MAPK activation were diminished. Furthermore, pre-treatment with fluvastatin, significantly attenuated observed Jurkat cell adhesion. These findings indicate novel mechanisms of CD4+ T-cells recruitment to activated endothelium via CD4 and CXCR4, which are modulated by statin.
Takano
Yoshio
Y
Department of Vascular Medicine, Tokyo Medical and Dental University, Japan.
Shimokado
Kentaro
K
Hata
Yuiro
Y
Yoshida
Masayuki
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002448:Cell Adhesion; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008213:Lymphocyte Activation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D015704:CD4 Antigens; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D005229:Fatty Acids, Monounsaturated; D015699:HIV Envelope Protein gp120; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D019718:Receptors, CXCR4; D000077340:Fluvastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3