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The Journal of Immunology, 2001, 167: 7009-7016.
Copyright © 2001 by The American Association of Immunologists

Salmonella Flagellin-Dependent Proinflammatory Responses Are Localized to the Conserved Amino and Carboxyl Regions of the Protein1

Tonyia D. Eaves-Pyles2,*,{dagger}, Hector R. Wong*, Kelli Odoms* and Richard B. Pyles{dagger},{ddagger}

Divisions of * Critical Care Medicine, and {dagger} Infectious Diseases, Children’s Hospital Research Foundation, Cincinnati, OH 45229; and {ddagger} Department of Pediatrics and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555.

Flagellin, the monomeric subunit of flagella, is an inducer of proinflammatory mediators. Bacterial flagellin genes have conserved domains (D1 and D2) at the N terminus and C terminus and a middle hypervariable domain (D3). To identify which domains induced proinflammatory activity, r6-histidine (6HIS)-tagged fusion constructs were generated from the Salmonella dublin (SD) fliC flagellin gene. A full-length r6HIS SD flagellin (6HIS flag) induced I{kappa}B{alpha} loss poststimulation and NF-{kappa}B activation in Caco-2BBe cells and was as potent as native-purified SD flagellin. IFN-{gamma}-primed DLD-1 cells stimulated with 1 µg/ml of 6HIS flag induced high levels of NO (60 ± 0.95 µM) comparable to the combination of IL-1{beta} and IFN-{gamma} (77 ± 1.2) or purified native SD flag (66.3 ± 0.98). Selected rSD flagellin proteins representing the D1, D2, or D3 domains alone or in combination were tested for proinflammatory properties. Fusion proteins representing the D3, amino, or carboxyl regions alone did not induce proinflammatory mediators. The results with a recombinant protein containing the amino D1 and D2 and carboxyl D1 and D2 separated by an Escherichia coli hinge (ND1-2/ECH/CD2) indicated that D1 and D2 were bioactive when coupled to an ECH element to allow protein folding. This chimera, but not the hinge alone, induced I{kappa}B{alpha} degradation, NF-{kappa}B activation, and NO and IL-8 production in two intestinal epithelial cell lines. ND1–2/ECH/CD2–1 also induced high levels of TNF-{alpha} (900 pg/ml) in human monocytes comparable to native SD flagellin (991.5 pg/ml) and 6HIS flag (987 pg/ml). The potent proinflammatory activity of flagellin, therefore, resides in the highly conserved N and C D1 and D2 regions.




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