Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Blazanin, Nicholas; Cheng, Tianyi; Carbajal, Steve; DiGiovanni, John

doi:10.1002/mc.23073

Cited by 22 publications

(19 citation statements)

References 101 publications

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“…UV radiation of skin induces keratinocyte expression of COX‐2, an enzyme responsible for metabolism of arachidonic acid into prostaglandin E 2 (PGE2). In both preclinical animal models and in clinical trials, COX‐2 is a key mediator in the promotion of UV‐irradiated keratinocytes into premalignant actinic keratoses and the progression of actinic keratosis (AKs) into KCs 20 . We wondered whether COX‐2 levels in skin and tumors might differ in C3H/HeN and C3H/HeJ mice.…”

Section: Resultsmentioning

confidence: 99%

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

Ahmad

Nasti

Rihan

et al. 2020

Molecular Carcinogenesis

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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.

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Section: Resultsmentioning

confidence: 99%

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

Ahmad

Nasti

Rihan

et al. 2020

Molecular Carcinogenesis

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“…Subsequently, the expression of several transcriptional factors is upregulated, especially interferon-responsive factors (IRFs). IRF-1 is the vital downstream component of STAT1 upon IFN-γ treatment [46,47]. In hepatocellular carcinoma, it was identified that two elements (IRE1/2) in the 5′-flanking region of the CD274 promoter were the binding sites of IRF-1, which participated in regulating PD-L1 transcription [48].…”

Section: Inflammatory Signaling Interferon (Ifn) and Il-6mentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

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“…The mechanisms underlying inflammation and melanin formation remain unclear at present. Exposure to acute SUV leads to IFNγ upregulation and downstream pSTAT1/IRF-1/uSTAT1 signaling in the epidermis and increases the proinflammatory chemokine mRNAs in the epidermis 21 , including Cxcl9, Cxcl10, and Ccl2. In addition, keratinocytes can change the melanin production of melanocytes by producing soluble factors under inflammatory conditions 22 .…”

Section: Discussionmentioning

confidence: 99%

Salidroside can target both P4HB-mediated inflammation and melanogenesis of the skin

Ding¹,

Zhang²,

Jin³

et al. 2020

Theranostics

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Rationale: Many external factors can induce the melanogenesis and inflammation of the skin. Salidroside (SAL) is the main active ingredient of Rhodiola , which is a perennial grass plant of the Family Crassulaceae. This study evaluated the effect and molecular mechanism of SAL on skin inflammation and melanin production. It then explored the molecular mechanism of melanin production under ultraviolet (UV) and inflammatory stimulation. Methods: VISIA skin analysis imaging system and DermaLab instruments were used to detect the melanin reduction and skin brightness improvement rate of the volunteers. UV-treated Kunming mice were used to detect the effect of SAL on skin inflammation and melanin production. Molecular docking and Biacore were used to verify the target of SAL. Immunofluorescence, luciferase reporter assay, CO-IP, pull-down, Western blot, proximity ligation assay (PLA), and qPCR were used to investigate the molecular mechanism by which SAL regulates skin inflammation and melanin production. Results: SAL can inhibit the inflammation and melanin production of the volunteers. SAL also exerted a protective effect on the UV-treated Kunming mice. SAL can inhibit the tyrosinase (TYR) activity and TYR mRNA expression in A375 cells. SAL can also regulate the ubiquitination degradation of interferon regulatory factor 1 (IRF1) by targeting prolyl 4-hydroxylase beta polypeptide (P4HB) to mediate inflammation and melanin production. This study also revealed that IRF1 and upstream stimulatory factor 1 (USF1) can form a transcription complex to regulate TYR mRNA expression. IRF1 also mediated inflammatory reaction and TYR expression under UV- and lipopolysaccharide-induced conditions. Moreover, SAL derivative SAL-plus (1-(3,5-dihydroxyphenyl) ethyl-β-d-glucoside) showed better effect on inflammation and melanin production than SAL. Conclusion: SAL can inhibit the inflammation and melanogenesis of the skin by targeting P4HB and regulating the formation of the IRF1/USF1 transcription complex. In addition, SAL-plus may be a new melanin production and inflammatory inhibitor.

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Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Cited by 22 publications

References 101 publications

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

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

Regulation of PD-L1 expression in the tumor microenvironment

Salidroside can target both P4HB-mediated inflammation and melanogenesis of the skin

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