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Infection and Immunity, December 2002, p. 6658-6664, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6658-6664.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Counteracting Interactions between Lipopolysaccharide Molecules with Differential Activation of Toll-Like Receptors

George Hajishengallis,1* Michael Martin,2 Robert E. Schifferle,1 and Robert J. Genco1

Department of Oral Biology, State University of New York at Buffalo, Buffalo, New York 14214,1 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 352942

Received 7 June 2002/ Returned for modification 10 July 2002/ Accepted 28 August 2002

We investigated counteracting interactions between the lipopolysaccharides (LPS) from Escherichia coli (Ec-LPS) and Porphyromonas gingivalis (Pg-LPS), which induce cellular activation through Toll-like receptor 4 (TLR4) and TLR2, respectively. We found that Ec-LPS induced tolerance in THP-1 cells to subsequent tumor necrosis factor alpha (TNF-{alpha}) and interleukin 1 beta (IL-1ß) induction by Pg-LPS, though the reverse was not true, and looked for explanatory differential effects on the signal transduction pathway. Cells exposed to Pg-LPS, but not to Ec-LPS, displayed persisting expression of IL-1 receptor-associated kinase without apparent degradation, presumably allowing prolonged relay of downstream signals. Accordingly, cells pretreated with Pg-LPS, but not with Ec-LPS, were effectively activated in response to subsequent exposure to either LPS molecule, as evidenced by assessing nuclear factor (NF)-{kappa}B activity. In fact, Pg-LPS primed THP-1 cells for enhanced NF-{kappa}B activation and TNF-{alpha} release upon restimulation with the same LPS. This was a dose-dependent effect and correlated with upregulation of surface TLR2 expression. Furthermore, we observed inhibition of NF-{kappa}B-dependent transcription in a reporter cell line pretreated with Ec-LPS and restimulated with Pg-LPS (compared to cells pretreated with medium only and restimulated with Pg-LPS), but not when the reverse treatment was made. Although Pg-LPS could not make cells tolerant to subsequent activation by Ec-LPS, Pg-LPS inhibited Ec-LPS-induced TNF-{alpha} and IL-6 release when the two molecules were added simultaneously into THP-1 cell cultures. Pg-LPS also suppressed P. gingivalis FimA protein-induced NF-{kappa}B-dependent transcription in the 3E10/huTLR4 reporter cell line, which does not express TLR2. This rules out competition for common signaling intermediates, suggesting that Pg-LPS may block component(s) of the TLR4 receptor complex. Interactions between TLR2 and TLR4 agonists may be important in the regulation of inflammatory reactions.

* Corresponding author. Mailing address: Department of Oral Biology, 135 Foster Hall, 3435 Main St., SUNY at Buffalo, Buffalo, NY 14214. Phone: (716) 829-3518. Fax: (716) 829-3942. E-mail: gh6{at}acsu.buffalo.edu.

Editor: B. B. Finlay

Infection and Immunity, December 2002, p. 6658-6664, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6658-6664.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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