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,
Divisions of
*
Critical Care Medicine, and
Infectious Diseases, Children’s Hospital Research Foundation, Cincinnati, OH 45229; and
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
B
loss poststimulation and NF-B activation in Caco-2BBe cells and was
as potent as native-purified SD flagellin.
IFN-
-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
and IFN- (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 IB
degradation, NF-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- (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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