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Infection and Immunity, August 2002, p. 4035-4044, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4035-4044.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interaction of Neisseria meningitidis with Human Meningeal Cells Induces the Secretion of a Distinct Group of Chemotactic, Proinflammatory, and Growth-Factor Cytokines

Myron Christodoulides,1* Benjamin L. Makepeace,1,{dagger} Kris A. Partridge,1,{ddagger} Davindaur Kaur,1 Mark I. Fowler,1 Roy O. Weller,2 and John E. Heckels1

Molecular Microbiology and Infection, Division of Infection, Inflammation and Repair,1 Clinical Neurosciences, University of Southampton Medical School, Southampton General Hospital, Southampton, S016 6YD, United Kingdom2

Received 28 January 2002/ Returned for modification 27 March 2002/ Accepted 26 April 2002

The interactions of Neisseria meningitidis with cells of the leptomeninges are pivotal events in the progression of bacterial leptomeningitis. An in vitro model based on the culture of human meningioma cells was used to investigate the role of the leptomeninges in the inflammatory response. Following challenge with meningococci, meningioma cells secreted specifically the proinflammatory cytokine interleukin-6 (IL-6), the CXC chemokine IL-8, the CC chemokines monocyte chemoattractant protein 1 (MCP-1) and regulated-upon-activation, normal-T-cell expressed and secreted protein (RANTES), and the cytokine growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). A temporal pattern of cytokine production was observed, with early secretion of IL-6, IL-8, and MCP-1 followed by later increases in RANTES and GM-CSF levels. IL-6 was induced equally by the interactions of piliated and nonpiliated meningococci, whereas lipopolysaccharide (LPS) had a minimal effect, suggesting that other, possibly secreted, bacterial components were responsible. Induction of IL-8 and MCP-1 also did not require adherence of bacteria to meningeal cells, but LPS was implicated. In contrast, efficient stimulation of RANTES by intact meningococci required pilus-mediated adherence, which served to deliver increased local concentrations of LPS onto the surface of meningeal cells. Secretion of GM-CSF was induced by pilus-mediated interactions but did not involve LPS. In addition, capsule expression had a specific inhibitory effect on GM-CSF secretion, which was not observed with IL-6, IL-8, MCP-1, or RANTES. Thus, the data demonstrate that cells of the leptomeninges are not inert but are active participants in the innate host response during leptomeningitis and that there is a complex relationship between expression of meningococcal components and cytokine induction.

* Corresponding author. Mailing address: Division of Infection, Inflammation and Repair, University of Southampton Medical School, Southampton General Hospital, Tremona Road, Southampton, S016 6YD, United Kingdom. Phone: 02380-798896. Fax: 02380-796992. E-mail: mc4{at}soton.ac.uk.

Editor: J. D. Clements

{dagger} Present address: Veterinary Parasitology (Faculty of Veterinary Science), Division of Parasite & Vector Biology, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, United Kingdom.

{ddagger} Present address: University Orthopaedics, University of Southampton Medical School, Southampton General Hospital, Southampton, S016 6YD, United Kingdom.

Infection and Immunity, August 2002, p. 4035-4044, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4035-4044.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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