Advisor

Filipov, Nickolay

Committee Member

Chambers, Jay

Committee Member

Pinchukm Lesya

Committee Member

Carr, Russell

Committee Member

Pruett, Stephen

Date of Degree

1-1-2008

Document Type

Dissertation - Open Access

Major

Environmental Toxicology

Degree Name

Doctor of Philosophy

College

College of Veterinary Medicine

Abstract

Manganese (Mn) neurotoxicity has been recognized for a long time and it affects primarily the basal ganglia. However, only recently has inflammation, which is known to play an important role in neuropathology, been considered as part of its toxic mechanism. In the current study, we have shown that Mn-potentiation of inflammatory cytokines ( IL-6 and TNF-á) in microglia is not dependent on the activaton of the Toll-like receptor (TLR)-4 signaling pathway by lipolysaccharide (LPS), as potentiation by Mn is observed in microglia activated with agonists for other TLR, such as TLR2, TLR3, and TLR9. Furthermore, enhancement of inflammatory cytokine production by Mn is independent of the MyD88 signaling pathway , as Mn-potentiation in TLR3-activated microglia occurs by a signaling pathway which is MyD88- independent. Additionally, inhibition of p38, ERK, or JNK mitogen-activated protein Kinases (MAPK) prevented Mn-potentiation, which suggest that these MAPK are required for potentiation of inflammatory cytokines by Mn. We also observed that Mn exposure results in persistent activation of p38. The prolonged activation of p38 may be due to increased activation of the ‘upstream’ MAPK, mitogen-activated protein kinase kinase (MKK)-1/2 or MKK-4, or to decreased expression of the phosphatase, mitogen- activated protein kinase phosphatase-1 (MKP-1), that is responsible for deactivating p38. Overall, it appears that Mn potentiates microglial inflammatory cytokine output in conjunction with diverse stimuli by an unknown mechanism, but likely involving MAPK and perhaps extending their activation, that of p38 in particular. This ability of Mn to potentiate brain inflammation should be considered as part of its neurotoxic mechanism.

URI

https://hdl.handle.net/11668/15505

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