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The Journal of Neuroscience, October 27, 2004, 24(43):9623-9631; doi:10.1523/JNEUROSCI.2392-04.2004

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Cellular/Molecular
Cell-Specific Expression and Lipopolysaccharide-Induced Regulation of Tumor Necrosis Factor (TNF) and TNF Receptors in Rat Dorsal Root Ganglion

Yanzhang Li, Ailing Ji, Eberhard Weihe, and Martin K.-H. Schäfer

Department of Molecular Neuroscience, Institute of Anatomy and Cell Biology, Philipps University Marburg, 35033 Marburg, Germany

The proinflammatory and lipopolysaccharide (LPS)-inducible cytokine tumor necrosis factor (TNF) has been shown to enhance primary sensory nociceptive signaling. However, the precise cellular sites of TNF and TNF receptor synthesis are still a matter of controversy. Therefore, we differentiated the neuronal and non-neuronal sites of TNF, TNFR1, and TNFR2 mRNA synthesis in dorsal root ganglion (DRG) of control rats and evaluated how their expression is altered under systemic challenge with LPS. In situ hybridization (ISH), RT-PCR analysis of laser-microdissected cells, and immunocytochemistry revealed absence of TNF from DRG neurons and LPS-induced expression of TNF exclusively in a subpopulation of non-neuronal DRG cells. Using RT-PCR and Northern blotting TNFR1 and TNFR2 mRNAs were found to be constitutively expressed and increased after LPS. TNFR1 mRNA was expressed in virtually all neurons and in non-neuronal cells with increased levels after LPS in both. TNFR2 was exclusively expressed and regulated in non-neuronal cells. RT-PCR analysis of microdissected DRG neurons and of the sensory neuronal cell line F11 confirmed the neuronal expression of TNFR1 and excluded that of TNFR2. Double ISH revealed varying levels of TNFR1 mRNA in virtually all DRG neurons including putative nociceptive neurons coding for calcitonin gene-related peptide, substance P, or vanilloid receptor 1. Taken together, we provide evidence that non-neuronally synthesized TNF may directly act on primary afferent neurons via TNFR1 but not TNFR2. This is likely to be relevant under conditions of inflammatory pain and infections accompanied by widespread TNF synthesis and release and may drive sickness behavior.

Key words: cytokine; neuroimmune; primary afferent; neuropeptide; vanilloid receptor; pain

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Received June 17, 2004; revised September 9, 2004; accepted September 10, 2004.

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