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.

TLR4 gene polymorphisms in Egyptian vitiligo patients: insights into emerging association with clinical activity, family history, and response to therapy

“…A recent study proved that TLR4-mediated inflammation may potentiate the effects of UVB and even increase the incidence of UVB-induced skin cancers. Accordingly, inhibition of TLR4-mediated immune reactions could improve the therapeutic effects of UVB [ 42 ].…”

Toll-Like Receptor-4 Antagonist Enhances the Repair of Ultraviolet Radiation-Induced DNA Damage and Augments Anti-Tumor Immune Responses in Mice

“…Protein bands were visualized using the enhanced chemiluminescence detection system (iBright Western Blot imaging systems, Thermofisher Scientific, Waltham, MA, USA). To verify equal protein loading and transfer of proteins from gel to membrane, the blots were stripped and reprobed for β-actin [ 18 , 20 ]. The band density was analyzed using IMAGE J software provided by the NIH and the values were normalized to the β-actin band density.…”

“…Mice were monitored for tumors on a weekly basis. In all experiments, mice that were not exposed to UVB were used as controls [ 20 , 24 ].…”

“…We have also shown that loss of TLR4 resulted in prevention of UVB-induced suppression of immune responses by inhibiting development of regulatory T-cells [ 19 ]. We have shown that TLR4 deficiency inhibited UVB-induced chronic inflammation and reduced immune suppression in tumor microenvironment, resulting in enhanced tumor development [ 20 ]. In this study, we determined the role of TLR4 inhibitor, TAK-242, in the repair of DNA damage, inhibition of inflammation, and augmentation of cutaneous immune responses all of which contribute to prevention of photocarcinogenesis in mice.…”

Immune-associated molecular occurrence and prognosis predictor of hepatocellular carcinoma: an integrated analysis of GEO datasets

“…Immune-associated genetic dysfunction is the key cause of cancer development and occurrence [8,9]. Ahmad et al found that Toll-like eceptor 4 can suppress antitumor response and trigger the development of ultraviolt B-induced skin cancer [10]; Nicoud et al [11] discovered that histamine H 4 receptor can upregulate the proportion of cluster of differentiation (CD)4 + CD25 + FoxP3 + regulatory T cells and promote an immunosuppressive milieu. Immune-associated predictors have been shown to accurately predict the occurrence or prognosis of ovarian cancer and colorectal cancer [12][13][14].…”