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Toll-like Receptor 4 Mediates an Antitumor Host Response Induced by Salmonella choleraesuis

Authors' Affiliations: Departments of ¹ Microbiology and Immunology and ² Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

Requests for reprints: Ai-Li Shiau, Department of Microbiology and Immunology, National Cheng Kung University Medical College, 1 Dashiue Road, Tainan 70101, Taiwan. Phone: 886-6-2353535, ext. 5629; Fax: 886-6-2363715; E-mail: alshiau{at}mail.ncku.edu.tw.

Purpose: We have shown tumor-targeting and antitumor activities of an attenuated Salmonella choleraesuis in various tumor models. Meanwhile, host factors, including innate and adaptive immune responses, play roles in Salmonella-induced antitumor activity. Toll-like receptor 4 (TLR4) is identified as a signaling receptor for lipopolysaccharide derived from Gram-negative bacteria. However, the detailed mechanism of the S. choleraesuis–induced antitumor immune response via TLR4 remained uncertain.

Experimental Design: Herein, we used wild-type C3H/HeN mice and TLR4-deficient C3H/HeJ mice to study the role of TLR4 in the antitumor immune responses induced by S. choleraesuis.

Results: The amounts of S. choleraesuis were cleared more rapidly from the normal organs in C3H/HeN mice than those in C3H/HeJ mice. Tumors in C3H/HeN mice treated with S. choleraesuis were significantly smaller than those treated with PBS. By contrast, in TLR4-deficient mice, there was a slight difference in inhibition of tumor growth. Meanwhile, we found that S. choleraesuis significantly up-regulated IFN-, IFN-inducible chemokines CXCL9 (MIG), and CXCL10 (IP-10) productions in C3H/HeN mice, but not in C3H/HeJ mice. Furthermore, immunohistochemical staining of the tumors revealed less intratumoral microvessel density, more infiltration of macrophages, neutrophils, CD4⁺ and CD8⁺ T cells, and cell death in C3H/HeN mice after S. choleraesuis treatment compared with those in C3H/HeJ mice. The interaction between TLR4 and S. choleraesuis seemed to polarize the T-cell response to a T helper 1–dominant state.

Conclusions: These results suggest TLR4 may play an important role in the molecular mechanism of S. choleraesuis–induced host antitumor responses.