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Infection and Immunity, October 2000, p. 5756-5763, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Systemic Neutralization of Interleukin-8 Markedly Reduces Neutrophilic Pleocytosis during Experimental Lipopolysaccharide-Induced Meningitis in Rabbits

Rachel A. Dumont,1,dagger Bruce D. Car,2,Dagger Nikolai N. Voitenok,3 Ursula Junker,1 Bernhard Moser,2 Oto Zak,1 and Terence O'Reilly1,*

Novartis Pharma Limited, CH-4002 Basel,1 and Theodor-Kocher Institute, University of Bern, CH-3012 Bern,2 Switzerland, and Fund for Molecular Hematology and Immunology, Moscow, Russia3

Received 31 January 2000/Returned for modification 24 April 2000/Accepted 3 July 2000

Interleukin-8 (IL-8) is elevated in the cerebrospinal fluid (CSF) of patients with meningitis and is proposed to participate in subarachnoid-space pleocytosis. However, intracisternal injection of IL-8 into rabbits failed to induce indices typical of meningitis (leukocyte, tumor necrosis factor, or protein accumulation in the CSF or histopathological changes), indicating that merely increasing the CSF level of this chemokine is insufficient to induce inflammation in this anatomical site. IL-8 treatment did not affect inflammatory responses to subsequently intracisternally administered lipopolysaccharide (LPS). IL-8 was chemotactic for rabbit neutrophils in vitro, and subcutaneous injection of IL-8 (diluted in buffer or CSF) proved the in vivo activity of this peptide and suggested the absence of an IL-8 inhibitor in normal rabbit CSF. LPS-dependent pleocytosis was only slightly diminished by intracisternally administered murine anti-rabbit IL-8 monoclonal antibody (MAb) WS-4 but was dramatically reduced by intravenously administered MAb. Therefore, elevated CSF IL-8 levels may contribute to, but cannot solely account for, neutrophil influx into the subarachnoid space during meningitis. However, inhibition of IL-8 activity of the bloodstream side of the blood-brain barrier effectively reduces pleocytosis, indicating a central role of IL-8 in neutrophil influx into CSF during bacterial meningitis. Thus, inhibition of IL-8 is a possible therapeutic target for adjunct treatment of meningitis.

* Corresponding author. Mailing address: Novartis Pharma AG, WKL 125.1.05, CH-4002 Basel, Switzerland. Phone: 41-61-696-3427. Fax: 41-61-696-6242. E-mail: terence.oreilly{at}pharma.novartis.com.

dagger Present address: Oregon Hearing Research Center, Oregon Health Sciences University, Portland, OR 97207.

Dagger Present address: DuPont Merck R&D, Stine-Haskell Research Center, Newark, DE 19174-0030.

Infection and Immunity, October 2000, p. 5756-5763, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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