HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Free Full Text (PDF) Free All Versions of this Article: 95/5/1873    most recent 00371.2003v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Campisi,, J. Articles by Fleshner, M. Search for Related Content PubMed PubMed Citation Articles by Campisi,, J. Articles by Fleshner, M.

Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge

¹Department of Integrative Physiology, ²Center for Neuroscience, and ³Department of Psychology, University of Colorado, Boulder, Colorado 80309-0354

Submitted 11 April 2003 ; accepted in final form 10 July 2003

Peripheral administration of a variety of inflammatory stimuli, such as endotoxin or cytokines, induces an orchestrated set of brain-mediated events referred to as the sickness response. The mechanism for how immune products signal the brain is not clear, but accumulating evidence supports the existence of neural as well as blood-borne pathways. Although endotoxin or cytokine administration results in sickness responses, few data exist regarding the role of circulating endotoxin or cytokines in the induction of sickness during a real bacterial infection. Thus the present studies examined whether subcutaneously administered Escherichia coli can activate sickness responses and whether circulating endotoxin and/or proinflammatory cytokines are a prerequisite for these responses. Male Sprague-Dawley rats were injected subcutaneously with one of three doses (2.5 x 10⁷, 2.5 x 10⁸, 2.5 x 10⁹ colony-forming units) of replicating E. coli, a ubiquitous bacterial strain, or vehicle. Core body temperature (T_c) and activity were measured for 3 days after the injection. A second set of groups of animals were killed 3, 6, 12, 18, 24, and 48 h after the injection, and blood samples and brains were collected. Injections dose dependently and consistently increased T_c and decreased activity, with increases in T_c beginning 4 h after the injection. In addition, E. coli significantly increased serum interleukin (IL)-1, IL-6, and tumor necrosis factor- and brain IL-1 levels beginning at the 6-h time point. Corticosterone and endotoxin were first elevated in the circulation at 3 and 18 h after the injection, respectively. Because fever onset preceded brain cytokine induction, we also examined cytokine levels in the serum, brain, and inflammation site 2 and 4 h after injection. Cytokines were elevated at the inflammation site but were not detectable in the serum or brain at 2 and 4 h. We conclude that subcutaneous injection of replicating E. coli induces a consistent and naturalistic infection that includes features of the sickness response as well as increases in circulating, brain, and inflammation site tissue cytokines. In addition, injection of replicating E. coli produces a robust fever and corticosterone response at a time when there are no detectable increases in circulating cytokines or endotoxin. These results suggest that elevated levels of circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response. Therefore, fever, activity reduction, and corticosterone elevation induced by E. coli infection may have been evoked by a neural, rather than a humoral, pathway from the periphery to the brain.

bacteria; tumor necrosis factor-; interleukin-1; immune-to-brain communication; Escherichia coli

This article has been cited by other articles:

				R. S. Munford Invited review: Detoxifying endotoxin: time, place and person Innate Immunity, April 1, 2005; 11(2): 69 - 84. [Abstract] [PDF]

				C. Rummel, T. Hubschle, R. Gerstberger, and J. Roth Nuclear translocation of the transcription factor STAT3 in the guinea pig brain during systemic or localized inflammation J. Physiol., June 1, 2004; 557(2): 671 - 687. [Abstract] [Full Text] [PDF]