Abstract
An antidiabetic drug of the thiazolidinedione class, rosiglitazone (RG) demonstrates anti-inflammatory properties in various brain pathologies. The mechanism of RG action in brain cells is not fully known. To unravel mechanisms of RG modulation of toll-like receptor (TLR) signaling pathways, we compare primary rat neuron and astrocyte cultures stimulated with the TLR4 agonist lipopolysaccharide (LPS) and the TLR3 agonist poly I:C (PIC). Both TLR agonists induced tumor necrosis factor (TNFα) release in astrocytes, but not in neurons. Neurons and astrocytes released interleukin-10 (IL-10) and prostaglandin E2 (PGE2) in response to LPS and PIC. RG decreased TLR-stimulated TNFα release in astrocytes as well as potentiated IL-10 and PGE2 release in both astrocytes and neurons. RG induced phosphorylation of p38 and JNK MAPK (mitogen-activated protein kinase) in neurons. The results reveal new role of RG as a modulator of resolution of neuroinflammation.
Highlights
Neuroinflammation is a form of innate immune response initiated by altered homeostasis within brain tissues
Our results showed that rosiglitazone induced p38 mitogen-activated protein kinase (MAPK), but not Jun N-terminal kinase (JNK), phosphorylation, and the effect was enhanced in the presence of LPS or poly I:C (PIC) in neurons, indicating possible molecular mechanism responsible for the observed alterations in IL-10 and prostaglandin E2 (PGE2) production
Our data show that RG acts on astrocytes as an anti-inflammatory and a pro-resolution substance by reducing TNFα and inducing IL-10 release, respectively, and as a pro-resolution substance in neurons
Summary
Neuroinflammation is a form of innate immune response initiated by altered homeostasis within brain tissues. Neuroinflammation accompanies all known neurological pathologies, including neurodegenerative diseases; post-ischemic neurodegeneration; and traumatic, metabolic, toxic and neoplastic disturbances [1,2,3]. Neuroinflammation has protective functions, its intrinsic cytotoxicity is recognized among major factors exacerbating brain pathologies of the brain. Detailed examination of neuroinflammation on cellular and molecular levels is crucial for new therapeutic targets discovery and development of effective treatment strategies. Toll-like receptor mediated signaling cascades play crucial role in peripheral inflammatory responses. Toll-like receptors (TLRs) can be activated both by various exogenous ligands (pathogen-associated molecular pattern or PAMP) and by an array of endogenous molecules generated and released during tissue damage (damage associated molecular pattern or DAMP) [4]. The mammalian TLR family is subdivided into two main groups: (1) cell surface TLRs
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