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Kati Huttunen,^1,2 Jukka Pelkonen,^2,3 Kristian Fogg Nielsen,⁴ Ulla Nuutinen,² Juha Jussila,¹ and Maija-Riitta Hirvonen¹

¹Department of Environmental Health, National Public Health Institute, Kuopio, Finland; ²Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland; ³Department of Clinical Microbiology, Kuopio University Hospital, Kuopio, Finland; ⁴Biocentrum-DTU, Technical University of Denmark, Lyngby, Denmark

Abstract
The microbial exposure associated with health complaints in moldy houses consists of a heterogeneous group of components, including both living and dead bacteria, fungi, and their metabolites and active compounds. However, little is known about the interactions between different microbes and their metabolites, although the cytotoxicity and inflammatory potential of certain individual microbes have been reported. In this study, we investigated the inflammatory responses of mouse RAW264.7 macrophages after exposure to six indoor air microbes (Aspergillus versicolor, Penicillium spinulosum, Stachybotrys chartarum, Bacillus cereus, Mycobacterium terrae, and Pseudomonas fluorescens) alone and together with the actinomycete Streptomyces californicus. The production of nitric oxide, levels of the proinflammatory cytokines tumor necrosis factor (TNF-) and interleukin-6 (IL-6) , and cytotoxicity were measured. The coexposure to Sta. chartarum and Str. californicus caused a synergistic increase in the production of IL-6 but not other cytokines. In further experiments, the metabolites from Sta. chartarum or from closely related fungi (atranones B and E, satratoxin G, trichodermin, 7--hydroxytrichodermol, staplabin, and SMTP-7) and the known fungal toxins sterigmatocystin, citrinin, and ochratoxin A were each tested with Str. californicus. The testing revealed a synergistic response in TNF- and IL-6 production after coexposure to Str. californicus with both trichodermin and 7--hydroxytrichodermol. Finally, the synergistic inflammatory response caused by Str. californicus and trichodermin together was studied by analyzing for the presence of nuclear factor-B (NF-B) in nuclear extracts of the exposed cells. The exposure to Str. californicus induced the binding of NF-B proteins to the NF-B consensus sequence as well as to the natural NF-B site of the IL-6 promoter. Adding trichodermin to the exposure did not increase the DNA binding. Key words: bacteria, fungi, inflammation, interaction, mycotoxins, toxicity. Environ Health Perspect 112:659-665 (2004) . doi:10.1289/ehp.6701 available via http://dx.doi.org/ [Online 20 January 2004]

Address correspondence to K. Huttunen, Division of Environmental Health, National Public Health Institute, P.O. Box 95, Neulaniementie 4, FIN-70701 Kuopio, Finland. Telephone: 358-17-201320. Fax: 358-17-201265. E-mail: Kati.Huttunen@ktl.fi

We thank A. Rönkkö and R. Tiihonen for their excellent technical assistance.

This study was supported by the Academy of Finland, the Finnish Research Programme on Environmental Health, and the Juha Vainio Foundation.

The authors declare they have no competing financial interests.

Received 26 August 2003 ; accepted 20 January 2004.