Toll-like receptor-4 deficiency inhibits ultraviolet radiation-induced tumor development by modulation of immune and inflammatory responses.

Abstract

Ultraviolet (UV) B irradiation of the skin induces acute inflammation, as characterized by erythema, edema, and immunosuppression, and is subsequently linked to the progression of skin cancer. Toll-like receptor 4 (TLR4), a component of innate immunity, has been shown to play an important role in cancer. To elucidate the role of TLR4 in UVB-induced tumor development, TLR4-proficient (C3H/HeN) and TLR4-deficient (C3H/HeJ) mice were exposed to multiple doses of UVB radiation (200 mJ/cm2 ) for 40 weeks. Photocarcinogenesis was retarded in terms of tumor incidence, and tumor latency, in mice deficient in TLR4 compared with TLR4-proficient mice, whereas significantly greater numbers of tumors occurred in TLR4-proficient mice. There was significant upregulation of inflammatory markers like COX-2, PGE2 , S100A8, and S100A9 in the skin of TLR4-proficient mice than the skin of TLR4-deficient mice. Furthermore, we found that TLR4-proficient mice had a significantly higher number of Gr1+CD11b+ myeloid cells CD4+CD25+ regulatory T-cells than TLR4-deficient mice. Furthermore, the levels of interferon (IFN)-γ cytokine was increased and the levels of interleukin (IL)-4, IL-10, and IL-17 cytokines were decreased in serum, skin, and tumor lysates of TLR4-deficient mice in comparison with samples from TLR4-proficient mice. Together, our data indicate that TLR4-mediated inflammation may cause suppression of antitumor responses and trigger the development of UVB-induced skin cancers. Thus, strategies to inhibit TLR4-mediated immune suppression may allow us to develop preventive and therapeutic approaches for the management of UVB-induced cutaneous tumors.

• Authors: Israr Ahmad, Tahseen H Nasti, Heba M Rihan, Hugo Jimenez, Craig A Elmets, Nabiha Yusuf
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 60 Issue 1 Pg. 60-70 (01 2021) ISSN: 1098-2744 [Electronic] United States
• PMID: 33283918 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Tlr4 protein, mouse
• Toll-Like Receptor 4

Topics

• Animals
• Carcinogenesis (genetics, immunology, radiation effects)
• Gene Deletion
• Immunity
• Inflammation (etiology, genetics, immunology)
• Mice
• Skin Neoplasms (etiology, genetics, immunology)
• Toll-Like Receptor 4 (genetics, immunology)
• Ultraviolet Rays (adverse effects)