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Clinical and Diagnostic Laboratory Immunology, March 2002, p. 403-411, Vol. 9, No. 2
1071-412X/02/$04.00+0     DOI: 10.1128/CDLI.9.2.403-411.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Dependence of Bacterial Protein Adhesins on Toll-Like Receptors for Proinflammatory Cytokine Induction

George Hajishengallis,1* Michael Martin,2 Hakimuddin T. Sojar,1 Ashu Sharma,1 Robert E. Schifferle,1 Ernesto DeNardin,1 Michael W. Russell,3 and Robert J. Genco1

Departments of Oral Biology,1 Microbiology, State University of New York at Buffalo, Buffalo, New York 14214,3 Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 352942

Received 28 June 2001/ Returned for modification 5 November 2001/ Accepted 30 December 2001

Toll-like receptors (TLRs) are important signal transducers that mediate inflammatory reactions induced by microbes through pattern recognition of virulence molecules such as lipopolysaccharide (LPS) and lipoproteins. We investigated whether proinflammatory cytokine responses induced by certain bacterial protein adhesins may also depend on TLRs. In differentiated THP-1 mononuclear cells stimulated by LPS-free recombinant fimbrillin (rFimA) from Porphyromonas gingivalis, cytokine release was abrogated by monoclonal antibodies (MAbs) to CD14 and TLR4 but not to TLR2. Similar experiments using anti-ß2 integrin MAbs suggested that ß2 integrins (CD11/CD18) also play a role in cytokine induction by rFimA or native fimbriae. Minor fimbriae (distinct from the fimA-encoded major fimbriae) of P. gingivalis induced proinflammatory cytokine release in a CD14- and TLR2-dependent mode. Cytokine induction by BspA, a leucine-rich repeat protein from Bacteroides forsythus, depended heavily on CD14 and TLR2. We also found that the ability of the streptococcal protein AgI/II to stimulate cytokine release depended partially on CD14 and TLR4, and the AgI/II segment that possibly interacts with these receptors was identified as its N-terminal saliva-binding region. When THP-1 cells were exposed to rFimA for 24 h, surface expression of CD14 and CD18 was decreased and the cells became hyporesponsive to cytokine induction by a second challenge with rFimA. However, tolerance induction was abolished when the THP-1 cells were pretreated with rFimA in the presence of either anti-CD14 MAb or anti-TLR4 MAb. Induction of cross-tolerance between rFimA and LPS correlated with downregulation of the pattern recognition receptors involved. Our data suggest that the CD14-TLR2/4 system is involved in cytokine production and tolerance induction upon interaction with certain proinflammatory bacterial protein adhesins.

* 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) 829-2387. E-mail: gh6{at}acsu.buffalo.edu.

Clinical and Diagnostic Laboratory Immunology, March 2002, p. 403-411, Vol. 9, No. 2
1071-412X/02/$04.00+0     DOI: 10.1128/CDLI.9.2.403-411.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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