Tumor-promoting role of TGFβ1 signaling in ultraviolet B-induced skin carcinogenesis is associated with cutaneous inflammation and lymph node migration of dermal dendritic cells
Autor: | Javed Mohammed, Anand Ravindran, Adam B. Glick, Andrew J. Gunderson, Xiao Cui |
---|---|
Rok vydání: | 2013 |
Předmět: |
Male
Cancer Research Neoplasms Radiation-Induced Skin Neoplasms Ultraviolet Rays medicine.medical_treatment Receptor Transforming Growth Factor-beta Type I CD11c Original Manuscript Dermatitis Mice Transgenic Smad Proteins Inflammation Protein Serine-Threonine Kinases Biology medicine.disease_cause Transforming Growth Factor beta1 Mice medicine Animals Phosphorylation Mice Hairless integumentary system Dendritic Cells General Medicine Dendritic cell Transforming growth factor beta Flow Cytometry Hairless Cytokine Immunology Cancer research biology.protein Lymph Nodes medicine.symptom Signal transduction Carcinogenesis Receptors Transforming Growth Factor beta Signal Transduction |
Zdroj: | Carcinogenesis. 35:959-966 |
ISSN: | 1460-2180 0143-3334 |
Popis: | Transforming growth factor beta 1 (TGFβ1) is a pleiotropic cytokine in the skin that can function both as a tumor promoter and suppressor in chemically induced skin carcinogenesis, but the function in ultraviolet B (UVB) carcinogenesis is not well understood. Treatment of SKH1 hairless mice with the activin-like kinase 5 (ALK5) inhibitor SB431542 to block UVB-induced activation of cutaneous TGFβ1 signaling suppressed skin tumor formation but did not alter tumor size or tumor cell proliferation. Tumors that arose in SB-treated mice after 30 weeks had significantly reduced percentage of IFNγ(+) tumor-infiltrating lymphocytes compared with control mice. SB431542 blocked acute and chronic UVB-induced skin inflammation and T-cell activation in the skin-draining lymph node (SDLN) and skin but did not alter UVB-induced epidermal proliferation. We tested the effect of SB431542 on migration of skin dendritic cell (DC) populations because DCs are critical mediators of T-cell activation and cutaneous inflammation. SB431542 blocked (i) UVB-induced Smad2 phosphorylation in dermal DC (dDC) and (ii) SDLN and ear explant migration of CD103(+) CD207(+) and CD207(-) skin DC subsets but did not affect basal or UV-induced migration of Langerhans cells. Mice expressing a dominant-negative TGFβ type II receptor in CD11c(+) cells had reduced basal and UVB-induced SDLN migration of CD103(+) CD207(+) and CD207(-) DC subsets and a reduced percentage of CD86(high) dDC following UVB irradiation. Together, these suggest that TGFβ1 signaling has a tumor-promoting role in UVB-induced skin carcinogenesis and this is mediated in part through its role in UVB-induced migration of dDC and cutaneous inflammation. |
Databáze: | OpenAIRE |
Externí odkaz: |