TY - JOUR
T1 - A regulatory role for astrocytes in HIV-1 encephalitis
T2 - An overexpression of eicosanoids, platelet-activating factor, and tumor necrosis factor-α by activated HIV-1-infected monocytes is attenuated by primary human astrocytes
AU - Nottet, H. S.L.M.
AU - Jett, M.
AU - Flanagan, C. R.
AU - Zhai, Q. H.
AU - Persidsky, Y.
AU - Rizzino, A.
AU - Bernton, E. W.
AU - Genis, P.
AU - Baldwin, T.
AU - Schwartz, J.
AU - LaBenz, C. J.
AU - Gendelman, H. E.
PY - 1995
Y1 - 1995
N2 - HIV-1-infected brain macrophages participate in neurologic dysfunction through their continual secretion of neurotoxins. We previously demonstrated that astroglial cells activate HIV-1-infected monocytes to produce such neurotoxic activities. In this study, the mechanism underlying these monocyte secretory activities was unraveled and found dependent on HIV-1's ability to prime monocytes for activation. LPS stimulation of HIV-1-infected monocytes resulted in an overexpression of eicosanoids, platelet-activating factor (PAF), and TNF-α. This was dependent on the level of HIV-1 infection and monocyte stimulation. Cell to cell interactions between activated virus- infected monocytes and primary human astrocytes reduced monocyte secretions. The capacity of astrocytes to deactivate monocytes was, notably, TGF-β independent. Although astrocytes constitutively produced latent TGF-β2, HIV- 1-infected monocytes neither affected TGF-β2 production nor converted it into a bioactive molecule. Furthermore, addition of rTGF-β1 or rTGF-β2 or its Abs to LPS-stimulated monocyte-astrocyte mixtures had no effect on monokine production. In contrast, addition of rIL-10 to LPS-stimulated monocytes produced a dose-dependent decrease in TNF-α. IL-10 mRNAs were detected in monocytes, but not astrocytes, following LPS treatment. These results suggest that macrophage activation, a major component of HIV-1 infection in the brain, precipitates neuronal injury by causing virus- infected cells to synthesize neurotoxins. The neurotoxins produced by monocytes are then regulated by astrocytes. Astrocytes therefore, can play either positive or negative roles for disease depending on prior macrophage activation. These findings begin to unravel the cellular control mechanisms that influence cognitive and motor dysfunctions in HIV-1-infected individuals.
AB - HIV-1-infected brain macrophages participate in neurologic dysfunction through their continual secretion of neurotoxins. We previously demonstrated that astroglial cells activate HIV-1-infected monocytes to produce such neurotoxic activities. In this study, the mechanism underlying these monocyte secretory activities was unraveled and found dependent on HIV-1's ability to prime monocytes for activation. LPS stimulation of HIV-1-infected monocytes resulted in an overexpression of eicosanoids, platelet-activating factor (PAF), and TNF-α. This was dependent on the level of HIV-1 infection and monocyte stimulation. Cell to cell interactions between activated virus- infected monocytes and primary human astrocytes reduced monocyte secretions. The capacity of astrocytes to deactivate monocytes was, notably, TGF-β independent. Although astrocytes constitutively produced latent TGF-β2, HIV- 1-infected monocytes neither affected TGF-β2 production nor converted it into a bioactive molecule. Furthermore, addition of rTGF-β1 or rTGF-β2 or its Abs to LPS-stimulated monocyte-astrocyte mixtures had no effect on monokine production. In contrast, addition of rIL-10 to LPS-stimulated monocytes produced a dose-dependent decrease in TNF-α. IL-10 mRNAs were detected in monocytes, but not astrocytes, following LPS treatment. These results suggest that macrophage activation, a major component of HIV-1 infection in the brain, precipitates neuronal injury by causing virus- infected cells to synthesize neurotoxins. The neurotoxins produced by monocytes are then regulated by astrocytes. Astrocytes therefore, can play either positive or negative roles for disease depending on prior macrophage activation. These findings begin to unravel the cellular control mechanisms that influence cognitive and motor dysfunctions in HIV-1-infected individuals.
UR - http://www.scopus.com/inward/record.url?scp=0028930457&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028930457&partnerID=8YFLogxK
M3 - Article
C2 - 7897236
AN - SCOPUS:0028930457
VL - 154
SP - 3567
EP - 3581
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -