CCL3L1 prevents gp120-induced neuron death via the CREB cell signaling pathway.
Neurodegeneration is a characteristic feature of AIDS dementia complex and is commonly associated with neuronal death in the brains of both pediatric and adult patients. Neuronal death associated with AIDS dementia complex can be induced by the HIV-1 protein gp120, but the underlying signal transduction mechanism remains unclear, especially for HIV-1 subtypes commonly seen in China. We have now demonstrated that the human CC ligand 3-like protein 1 (CCL3L1), a member of the CC chemokine family, appears to protect neuronal cultures through its ability to attenuate gp120-induced neuronal death. We found that (i) both pCREB levels and Bcl-2 expression are up-regulated in neuronal culture following treatment with CCL3L1 plus gp120; (ii) CCL3L1 induces cell survival via phosphorylation of CREB by way of the PKA and CaMKI/CaMKIV cell signaling pathways; (iii) transcription of the cell survival gene bcl-2 is induced by pCREB; and (iv) CCL3L1 protects cultured neurons against CCR5-mediated excitotoxicity induced by gp120. Thus, the CCL3L1/bcl-2-regulated anti-apoptotic pathway significantly contributes to reduction of HIV-1/gp120-induced neuronal apoptosis, and therefore, CCL3L1 should be further investigated as a potential chemokine to protect against neuronal injury in gp120-related neuronal toxicity.
Chun
Huang
H
STD/AIDS Research Center, Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
Hao
Wu
W
Honghai
Zhang
Z
Ning
Li
L
Yasong
Wu
W
Chen
Dexi
D
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation
C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D017362:Cyclic AMP Response Element-Binding Protein; D015699:HIV Envelope Protein gp120; D019253:Proto-Oncogene Proteins c-bcl-2; D019713:Receptors, CCR5; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4