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TLR2 Expression in Astrocytes Is Induced by TNF-- and NF-B-Dependent Pathways¹

Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205

Astrocytes participate in CNS innate immune responses as evident by their ability to produce a wide array of inflammatory mediators upon exposure to diverse stimuli. Although we have established that astrocytes use TLR2 to signal inflammatory mediator production in response to Staphylococcus aureus, a common etiological agent of CNS infections, the signal transduction pathways triggered by this pathogen and how TLR2 expression is regulated remain undefined. Three disparate inhibitors that block distinct steps in the NF-B pathway, namely SC-514, BAY 11-7082, and caffeic acid phenethyl ester, attenuated NO, TNF-, and CXCL2 release from S. aureus-activated astrocytes. Among these proinflammatory mediators, autocrine/paracrine TNF- was pivotal for augmenting TLR2 expression, since receptor levels were not elevated in astrocytes isolated from TNF- knockout mice upon bacterial exposure. Since TLR2 is critical for signaling astrocytic cytokine production in response to S. aureus, we evaluated the effect of TNF- loss on proinflammatory mediator release. Interestingly, among the molecules assayed, only NO production was significantly attenuated in TNF- knockout astrocytes compared with wild-type cells. Similar results were obtained following LPS treatment, suggesting that TNF- is an important regulator of astrocytic TLR2 expression and NO release in response to diverse microbial stimuli. In addition, NF-B inhibitors attenuated TNF--induced TLR2 expression in astrocytes. Overall, this study suggests that two important anti-bacterial effector molecules, TLR2 and NO, are regulated, in part, by NF-B-dependent autocrine/paracrine effects of TNF- in astrocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Mental Health (Grant R01 MH65297) and Neurological Disorders and Stroke (Grant R01 NS055385) (to T.K.) and the National Institute of Neurological Disorders and Stroke supported Core Facility at University of Arkansas for Medical Sciences (Grant P30 NS047546).

² Address correspondence and reprint requests to Dr. Tammy Kielian at the current address: University of Nebraska Medical Center, Department of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68128. E-mail address: tkielian{at}unmc.edu

³ Abbreviations used in this paper: IKK, inhibitor of B kinase; CAPE, caffeic acid phenethyl ester; WT, wild type; iNOS, inducible NO synthase; KO, knockout; ROS, reactive oxygen species.

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