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HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms

BACKGROUND: Infection with human immunodeficiency virus type-1 (HIV)-1 leads to some form of HIV-1-associated neurocognitive disorders (HAND) in approximately half of the cases. The mechanisms by which astrocytes contribute to HIV-1-associated dementia (HAD), the most severe form of HAND, still rema...

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Autores principales: Mamik, Manmeet K, Banerjee, Sugato, Walseth, Timothy F, Hirte, Renee, Tang, Lin, Borgmann, Kathleen, Ghorpade, Anuja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3247131/
https://www.ncbi.nlm.nih.gov/pubmed/22027397
http://dx.doi.org/10.1186/1742-2094-8-145
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author Mamik, Manmeet K
Banerjee, Sugato
Walseth, Timothy F
Hirte, Renee
Tang, Lin
Borgmann, Kathleen
Ghorpade, Anuja
author_facet Mamik, Manmeet K
Banerjee, Sugato
Walseth, Timothy F
Hirte, Renee
Tang, Lin
Borgmann, Kathleen
Ghorpade, Anuja
author_sort Mamik, Manmeet K
collection PubMed
description BACKGROUND: Infection with human immunodeficiency virus type-1 (HIV)-1 leads to some form of HIV-1-associated neurocognitive disorders (HAND) in approximately half of the cases. The mechanisms by which astrocytes contribute to HIV-1-associated dementia (HAD), the most severe form of HAND, still remain unresolved. HIV-1-encephalitis (HIVE), a pathological correlate of HAD, affects an estimated 9-11% of the HIV-1-infected population. Our laboratory has previously demonstrated that HIVE brain tissues show significant upregulation of CD38, an enzyme involved in calcium signaling, in astrocytes. We also reported an increase in CD38 expression in interleukin (IL)-1β-activated astrocytes. In the present investigation, we studied regulatory mechanisms of CD38 gene expression in astrocytes activated with HIV-1-relevant stimuli. We also investigated the role of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB in astrocyte CD38 regulation. METHODS: Cultured human astrocytes were transfected with HIV-1(YU-2 )proviral clone and levels of CD38 mRNA and protein were measured by real-time PCR gene expression assay, western blot analysis and immunostaining. Astrocyte activation by viral transfection was determined by analyzing proinflammatory chemokine levels using ELISA. To evaluate the roles of MAPKs and NF-κB in CD38 regulation, astrocytes were treated with MAPK inhibitors (SB203580, SP600125, U0126), NF-κB interfering peptide (SN50) or transfected with dominant negative IκBα mutant (IκBαM) prior to IL-1β activation. CD38 gene expression and CD38 ADP-ribosyl cyclase activity assays were performed to analyze alterations in CD38 levels and function, respectively. RESULTS: HIV-1(YU-2)-transfection significantly increased CD38 mRNA and protein expression in astrocytes (p < 0.01) in a dose-dependent manner and induced astrocyte activation. IL-β-activation of HIV-1(YU-2)-transfected astrocytes significantly increased HIV-1 gene expression (p < 0.001). Treatment with MAPK inhibitors or NF-κB inhibitor SN50 abrogated IL-1β-induced CD38 expression and activity in astrocytes without altering basal CD38 levels (p < 0.001). IκBαM transfection also significantly inhibited IL-1β-mediated increases in CD38 expression and activity in astrocytes (p < 0.001). CONCLUSION: The present findings demonstrate a direct involvement of HIV-1 and virus-induced proinflammatory stimuli in regulating astrocyte-CD38 levels. HIV-1(YU-2)-transfection effectively induced HIV-1p24 protein expression and activated astrocytes to upregulate CCL2, CXCL8 and CD38. In astrocytes, IL-1β-induced increases in CD38 levels were regulated through the MAPK signaling pathway and by the transcription factor NF-κB. Future studies may be directed towards understanding the role of CD38 in response to infection and thus its role in HAND.
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spelling pubmed-32471312011-12-29 HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms Mamik, Manmeet K Banerjee, Sugato Walseth, Timothy F Hirte, Renee Tang, Lin Borgmann, Kathleen Ghorpade, Anuja J Neuroinflammation Research BACKGROUND: Infection with human immunodeficiency virus type-1 (HIV)-1 leads to some form of HIV-1-associated neurocognitive disorders (HAND) in approximately half of the cases. The mechanisms by which astrocytes contribute to HIV-1-associated dementia (HAD), the most severe form of HAND, still remain unresolved. HIV-1-encephalitis (HIVE), a pathological correlate of HAD, affects an estimated 9-11% of the HIV-1-infected population. Our laboratory has previously demonstrated that HIVE brain tissues show significant upregulation of CD38, an enzyme involved in calcium signaling, in astrocytes. We also reported an increase in CD38 expression in interleukin (IL)-1β-activated astrocytes. In the present investigation, we studied regulatory mechanisms of CD38 gene expression in astrocytes activated with HIV-1-relevant stimuli. We also investigated the role of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB in astrocyte CD38 regulation. METHODS: Cultured human astrocytes were transfected with HIV-1(YU-2 )proviral clone and levels of CD38 mRNA and protein were measured by real-time PCR gene expression assay, western blot analysis and immunostaining. Astrocyte activation by viral transfection was determined by analyzing proinflammatory chemokine levels using ELISA. To evaluate the roles of MAPKs and NF-κB in CD38 regulation, astrocytes were treated with MAPK inhibitors (SB203580, SP600125, U0126), NF-κB interfering peptide (SN50) or transfected with dominant negative IκBα mutant (IκBαM) prior to IL-1β activation. CD38 gene expression and CD38 ADP-ribosyl cyclase activity assays were performed to analyze alterations in CD38 levels and function, respectively. RESULTS: HIV-1(YU-2)-transfection significantly increased CD38 mRNA and protein expression in astrocytes (p < 0.01) in a dose-dependent manner and induced astrocyte activation. IL-β-activation of HIV-1(YU-2)-transfected astrocytes significantly increased HIV-1 gene expression (p < 0.001). Treatment with MAPK inhibitors or NF-κB inhibitor SN50 abrogated IL-1β-induced CD38 expression and activity in astrocytes without altering basal CD38 levels (p < 0.001). IκBαM transfection also significantly inhibited IL-1β-mediated increases in CD38 expression and activity in astrocytes (p < 0.001). CONCLUSION: The present findings demonstrate a direct involvement of HIV-1 and virus-induced proinflammatory stimuli in regulating astrocyte-CD38 levels. HIV-1(YU-2)-transfection effectively induced HIV-1p24 protein expression and activated astrocytes to upregulate CCL2, CXCL8 and CD38. In astrocytes, IL-1β-induced increases in CD38 levels were regulated through the MAPK signaling pathway and by the transcription factor NF-κB. Future studies may be directed towards understanding the role of CD38 in response to infection and thus its role in HAND. BioMed Central 2011-10-25 /pmc/articles/PMC3247131/ /pubmed/22027397 http://dx.doi.org/10.1186/1742-2094-8-145 Text en Copyright ©2011 Mamik et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Mamik, Manmeet K
Banerjee, Sugato
Walseth, Timothy F
Hirte, Renee
Tang, Lin
Borgmann, Kathleen
Ghorpade, Anuja
HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms
title HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms
title_full HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms
title_fullStr HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms
title_full_unstemmed HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms
title_short HIV-1 and IL-1β regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-κB signaling mechanisms
title_sort hiv-1 and il-1β regulate astrocytic cd38 through mitogen-activated protein kinases and nuclear factor-κb signaling mechanisms
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3247131/
https://www.ncbi.nlm.nih.gov/pubmed/22027397
http://dx.doi.org/10.1186/1742-2094-8-145
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