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Smad3‐dependent signaling underlies the TGF‐β1‐mediated enhancement in astrocytic iNOS expression

Hamby, Mary E., Hewett, James A., Hewett, Sandra J.·2010·Glia
DOI 10.1002/glia.21005PMC PMC4451602
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Abstract

We previously demonstrated that transforming growth factor‐β1 (TGF‐β1), while having no effect alone, enhances nitric oxide (NO) production in primary, purified mouse astrocytes induced by lipopolysaccharide (LPS) plus interferon‐γ (IFN‐γ), by recruiting a latent population of astrocytes to respond, thereby enhancing the total number of cells that express Nos2. In this investigation, we evaluated the molecular signaling pathway by which this occurs. We found that purified murine primary astrocytes express mRNA for TGFβRII as well as the TGFβRI subunit activin‐like kinase 5 (ALK5), but not ALK1. Immunofluorescence microscopy confirmed the expression of TGFβRII and ALK5 protein in astrocytes. Consistent with ALK5 signaling, Smad3 accumulated in the nucleus of astrocytes as early as 30 min after TGF‐β1 (3 ng/mL) treatment and persisted upto 32 hr after TGF‐β1 administration. Addition of ALK5 inhibitors prevented TGF‐β1‐mediated Smad3 nuclear accumulation and NO production when given prior to the Nos2 induction stimuli, but not after. Finally, astrocyte cultures derived from Smad3 null mutant mice did not exhibit a TGF‐β1‐mediated increase in iNOS expression. Overall, this data suggests that ALK5 signaling and Smad3 nuclear accumulation is required for optimal enhancement of LPS plus IFNγ‐induced NO production in astrocytes by TGF‐β1. © 2010 Wiley‐Liss, Inc.

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  • TGF-β and their receptors are expressed at low levels by both neurons and glial cells, and their expression is upregulated in response to a wide range of neuronal insults and during aging.

    “TGF-β and their receptors are expressed at low levels by both neurons and glial cells42,43, and their expression is upregulated in response to a wide range of neuronal insults and during aging44,45.”

    From Identification of a unique TGF-β–dependent molecular and functional signature in microglia (2014) · cites this paper as [43]

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Authors
Hamby, M. E., Hewett, J. A., & Hewett, S. J.
Venue
Glia
Publisher
Wiley
Published
2010-05-05
Volume
58
Issue
11
Pages
1282-1291
ISSN
  • 0894-1491
  • 1098-1136
DOI
10.1002/glia.21005
PMC
PMC4451602
Cited by
24
References
3
Language
en
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Funders
National Institutes of Health: National Institute for Neurological Disorders and Stroke (NINDS) (NS036812, NS051445, 5T32NS041224)

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