Inflammatory cytokines and HIV-1-associated neurodegeneration: oncostatin-M produced by mononuclear cells from HIV-1-infected individuals induces apoptosis of primary neurons.
Neurologic abnormalities are common in HIV-1-infected patients and often represent the dominant clinical manifestation of pediatric AIDS. The neurological dysfunction has been directly related to CNS invasion by HIV-1 that is principally, if not exclusively, supported by blood-derived monocytes/macrophages and lymphocytes. By using primary long term cultures of human fetal sensory neurons as well as sympathetic precursors-like neuronal cells, we determined that blood-derived mononuclear cells from HIV-1-infected individuals spontaneously release soluble mediators that can potently inhibit the growth and survival of developing neurons as well as the viability of postmitotic neuronal cells by inducing apoptotic cell death. Analysis of the cytokines produced by lymphomonocytic cells, HIV-1 infected or activated, indicated that oncostatin M (oncM) is a major mediator of these effects. Since low TGF-beta1 concentrations were capable of enhancing oncM-mediated neuronal alterations, our data indicate that by acting in concert with other cytokines, oncM may induce neuronal demise in both the developing and the mature brain. Thus, this cytokine may contribute to the setting of the neuronal cell damage observed in HIV-1-infected individuals.
Ensoli
F
F
Department of Allergy and Clinical Immunology, University of Rome "La Sapienza," Rome, Italy. ensolifior@axrma.uniromal.it
Fiorelli
V
V
DeCristofaro
M
M
Santini Muratori
D
D
Novi
A
A
Vannelli
B
B
Thiele
C J
CJ
Luzi
G
G
Aiuti
F
F
D017209:Apoptosis; D001681:Biological Assay; D016207:Cytokines / Q000378:metabolism*; D053938:DNA Fragmentation; D004347:Drug Interactions; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D018836:Inflammation Mediators / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D016207:Cytokines; D018836:Inflammation Mediators; D009498:Neurotoxins; C508351:OSM protein, human; D010455:Peptides; D016212:Transforming Growth Factor beta; D053683:Oncostatin M