First paper with drawings !
http://iospress.metapress.com/content/y05258137g173l5v/
Transforming
Growth Factor β1 Modulates Amyloid β-Induced Glial Activation through
the Smad3-Dependent Induction of MAPK Phosphatase-1
B Flores and R von Bernhardi
Chronic neuroinflammation has been proposed as a driving force for
Alzheimer's disease (AD), which is characterized by amyloid-β (Aβ)
deposition, neurofibrillary tangles, neuronal loss, and activation of
glial cells. Persistent activation of mitogen-activated protein kinases
(MAPKs) and nuclear factor kappa B (NF-κB) pathway has been reported,
which induces an increased expression of inflammatory mediators.
Transforming growth factor β1 (TGFβ1) is an inflammation modulator whose
levels are increased in AD. However, its canonical signaling pathway,
Smad, appears to be impaired. Our previous findings indicate that TGFβ1
plays a key role in the pathogenesis of neuroinflammation, but the
molecular mechanisms underlying its effects are not completely
elucidated. Here, we studied the potential role of MKP-1, a phosphatase
that exerts negative regulation on MAPK signaling, in the modulatory
actions of TGFβ1. Using rat primary glial cultures, we found that
pretreatment with TGFβ1 for 48 h reduced the production of inflammatory
mediators induced by Aβ42, a result that was associated with
prevention of MAPK p38 activation, attenuation of NF-κB p65 nuclear
translocation, and an increase in MKP-1 levels. Moreover, suppression of
MKP-1 expression by siRNA and inhibition of Smad3 reversed the
modulation of inflammatory response exerted by TGFβ1. These results
indicate that TGFβ1 induces the expression of MKP-1 in glial cells
through the Smad pathway and inhibits MAPK and NF-κB signaling, thus
revealing a novel mechanism for the neuroprotective actions of TGFβ1.
Further research would be important in order to characterize the role of
this mechanism in the pathogenesis of AD.
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