Sickness behaviour is induced by a peripheral CXC-chemokine also expressed in multiple sclerosis and EAE.
Non-CNS chemokine production may contribute to previously unrecognised components of Multiple Sclerosis (MS) pathology. Here we show that IL-8, a neutrophil chemoattractant, is significantly increased in serum from individuals with MS, and that the rodent homolog of IL-8 (CXCL1) is expressed in the liver in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. The hepatic expression of CXCL1 in EAE is accompanied by neutrophil recruitment to the liver, and we show that this recruitment is a feature of post mortem liver tissue from MS patients, which is a previously unrecognised phenomenon. We speculated that the presence of peripheral CXC-chemokine expression might contribute to the sickness behaviours associated with MS, which are a significant contributor to morbidity. Peripheral, but not central, administration of CXCL1 to Wistar rats inhibited spontaneous activity in the open field and burrowing behaviour in a dose-dependent manner (5-45 microg). The expression of CXCL1 by the liver and the recruitment of neutrophils can be modelled by the intracerebral injection of IL-1beta. Here, we found that interferon-beta (IFN-beta) pretreatment significantly inhibited hepatic CXCL1 production and neutrophil recruitment to the liver induced by the microinjection of IL-1beta into the brain. Thus while the mechanism by which IFN-beta therapy suppresses disease in MS remains unclear, the data presented here suggests that the inhibition of hepatic chemokine synthesis may be a contributing factor.
Experimental Neuropathology, Department of Pharmacology, University of Oxford, Oxford, UK.
Sandra J
SJ
Campbell
Ute
U
Meier
Silvy
S
Mardiguian
Yanyan
Y
Jiang
Edward T
ET
Littleton
Adrian
A
Bristow
Jane
J
Relton
Thomas J
TJ
Connor
Daniel C
DC
Anthony
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D055809:Illness Behavior; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D016209:Interleukin-8 / Q000097:blood* / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009103:Multiple Sclerosis / Q000097:blood* / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D007155:Immunologic Factors; D053583:Interleukin-1beta; D016209:Interleukin-8; D016899:Interferon-beta