Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects.
High mobility group box 1 (HMGB1), an abundant, highly conserved cellular protein, is widely known as a nuclear DNA-binding protein. HMGB1 has been recently implicated as a proinflammatory cytokine because of its role as a late mediator of endotoxin lethality and ability to stimulate release of proinflammatory cytokines from monocytes. Production of central cytokines is a critical step in the pathway by which endotoxin and peripheral proinflammatory cytokines, including interleukin-1beta (IL-1) and tumor necrosis factor-alpha (TNF), produce sickness behaviors and fever. Intracerebroventricular (ICV) administration of HMGB1 has been shown to increase TNF expression in mouse brain and induce aphagia and taste aversion. Here we show that ICV injections of HMGB1 induce fever and hypothalamic IL-1 in rats. Furthermore, we show that intrathecal administration of HMGB1 produces mechanical allodynia (lowering of the response threshold to calibrated stimuli). Finally, while endotoxin (lipopolysaccharide, LPS) administration elevates IL-1 and TNF mRNA in various brain regions, HMGB1 mRNA is unchanged. It remains possible that HMGB1 protein is released in brain in response to LPS. Nonetheless, these data suggest that HMGB1 may play a role as an endogenous pyrogen and support the concept that HMGB1 has proinflammatory characteristics within the central nervous system.
O'Connor
Kevin A
KA
Department of Psychology and Center for Neuroscience, University of Colorado, Boulder, CO 80309, USA. koconnor@psych.colorado.edu
Hansen
Michael K
MK
Rachal Pugh
C
C
Deak
Molly M
MM
Biedenkapp
Joseph C
JC
Milligan
Erin D
ED
Johnson
John D
JD
Wang
Haichao
H
Maier
Steven F
SF
Tracey
Kevin J
KJ
Watkins
Linda R
LR
D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology*; D005334:Fever / Q000378:metabolism; D024243:HMGB1 Protein / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D051381:Rats
D002491:Central Nervous System Agents; D024243:HMGB1 Protein; D007375:Interleukin-1