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Infect Immun, March 1998, p. 1127-1134, Vol. 66, No. 3
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Salmonella Flagellin Induces Tumor Necrosis Factor Alpha in a Human Promonocytic Cell Line

Federica Ciacci-Woolwine, Ian C. Blomfield, Stephen H. Richardson, and Steven B. Mizel*

Department of Microbiology and Immunology, Wake Forest University Medical Center, Winston-Salem, North Carolina 27157

Received 29 September 1997/Returned for modification 19 November 1997/Accepted 30 December 1997

During infection of the gastrointestinal tract, salmonellae induce cytokine production and inflammatory responses which are believed to mediate tissue damage in the host. In a previous study, we reported that salmonellae possess the ability to stimulate tumor necrosis factor alpha (TNF-alpha ) accumulation in primary human monocytes, as well as in the human promonocytic cell line U38. In this model system, cytokine upregulation is not due to lipopolysaccharide but is mediated by a released protein. In the present study, TnphoA transposon mutagenesis was used to identify the TNF-alpha -inducing factor. A mutant Salmonella strain which lacks the ability to induce TNF-alpha was isolated from a TnphoA library. Genetic analysis of this mutant demonstrated that the hns gene has been interrupted by transposon insertion. The hns gene product is a DNA-binding protein that regulates the expression of a variety of unrelated genes in salmonellae. One of the known targets of histone-like protein H1 is flhDC, the master operon which is absolutely required for flagellar expression. Analysis of other nonflagellated mutant Salmonella strains revealed a correlation between the ability to induce TNF-alpha and the expression of the phase 1 filament subunit protein FliC. Complementation experiments demonstrated that FliC is sufficient to restore the ability of nonflagellated mutant Salmonella strains to upregulate TNF-alpha , whereas the phase 2 protein FljB appears to complement to a lesser extent. In addition, Salmonella FliC can confer the TNF-alpha -inducing phenotype on Escherichia coli, which otherwise lacks the activity. Furthermore, assembly of FliC into complete flagellar structures may not be required for induction of TNF-alpha .

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Wake Forest University Medical Center, Medical Center Blvd., Winston-Salem, NC 27157. Phone: (336) 716-4471. Fax: (336) 716-9928. E-mail: smizel{at}bgsm.edu.




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