VLAHAKIS S, BOU G, HEPPELMANN C, VLAHAKIS N, PAYA CV; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. I-1956.

Mayo Clinic, Rochester, MN

BACKGROUND: Chemokine receptors are essential for chemotaxis and for HIV entry into host cells. CXCR4, when bound by its natural ligand, Stromal Derived Factor (SDF) on CD4 T cells triggers cell chemotaxis, whereas when bound by X4 env, results in cell death. However, both SDF and X4 envelope induce neuron death via CXCR4. To understand this dichotomy of cell survival that is dependent on CXCR4 receptor function we have used SDF as a probe to elucidate signaling pathways triggered by CXCR4 in CD4 T cells and neurons. METHODS: Resting CD4 T cells were isolated from healthy human donors. CD4 T cells and hNT neurons (Stratagene) were pre-treated or not with inhibitors, and incubated with SDF in vitro. The percentage of chemotaxis was determined for CD4 T cells (2hr), and the percentage of cell death was determined at 1 day for CD4 T cells and 3 days for neurons. RESULTS: As we have previously shown, CD4 T cells treated with SDF triggered chemotaxis without cell death. Inhibiting PI3K/Akt phosphorylation with the inhibitor Wortmannin (WT) caused SDF treated CD4 T cells to die but did not block chemotaxis. This suggests that PI3k/Akt pathway conveys anti-apoptotic features to an SDF treated CD4 T cell. Furthermore, inhibiting p38 phosphorylation completely blocked the death observed in the SDF treated cells pre-incubated with WT. Neurons treated with SDF resulted in direct cell death. However, pre-incubating the neurons with the p38 inhibitor (SB203580) ablated the neuron cell death that resulted from SDF treatment. In addition, pre-treating the neurons with Insulin, thereby inducing Akt activation, also blocked the SDF mediated death. CONCLUSIONS: These results indicate that CXCR4 triggers a p38-dependent death-signaling pathway that is neutralized by the co-activation of PI3K/Akt. The balance between SDF induced survival and death prone signals in CD4 T cells and neurons will determine the fate of the primary CD4 T cell or of the neuron.

Publication Types:

• Meeting Abstracts

Keywords:

• 1-Phosphatidylinositol 3-Kinase
• Antigens, CD4
• CASP4 protein, human
• CD4-Positive T-Lymphocytes
• Caspases
• Cell Death
• Chemotaxis
• Humans
• In Vitro
• Neurons
• PIK3CA protein, human
• Phosphorylation
• Protein-Serine-Threonine Kinases
• Proto-Oncogene Proteins
• Receptors, CXCR4
• Signal Transduction
• T-Lymphocytes
• immunology

Other ID:

• GWAIDS0029696

UI: 102269328

From Meeting Abstracts