TNF-alpha, generated during the systemic inflammatory response, triggers a wide range of biological activities that mediate the neurologic manifestations associated with cancer and infection. Since this cytokine regulates ion channels in vitro (especially Kv1.3 and Kir2.1), we aimed to study Kv1.3 and Kir2.1 expression in brain in response to in vivo systemic inflammation. Cancer-induced cachexia and LPS administration increased plasma TNF-alpha. Kv1.3 and Kir2.1 expression was impaired in brain during cancer cachexia. However, LPS treatment induced Kv1.3 and downregulated Kir2.1 expression, and TNF-alpha administration mimicked these results. Experiments using TNF-alpha double receptor knockout mice demonstrated that the systemic inflammatory response mediates K(+) channel regulation in brain via TNF-alpha-dependent and -independent redundant pathways. In summary, distinct neurological alterations associated with systemic inflammation may result from the interaction of various cytokine pathways tuning ion channel expression in response to neurophysiological and neuroimmunological processes.

This study was supported by grants from the Ministerio de Ciencia y Tecnología, Spain (BFI2002-00764 to AF and BFI2002-02186 to J.M.A.) and the Ministerio de Sanidad, Spain (FIS 03/0100 to F.J.L.-S.), Generalitat de Catalunya, Catalonia, Spain (SGR00108 to J.M.A.) and the Universitat de Barcelona (to A.F.). R.V. and R.M.-C. hold a fellowship from the Universitat de Barcelona.