Loss of endogenous interleukin-12 activates survival signals in ultraviolet-exposed mouse skin and skin tumors.
Interleukin-12 (IL-12)-deficiency promotes photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. Here, we report that long-term exposure to ultraviolet (UV) radiation resulted in enhancement of the levels of cell survival kinases, such as phosphatidylinositol 3-kinase (PI3K), Akt (Ser(473)), p-ERK1/2, and p-p38 in the skin of IL-12p40 knockout (IL-12 KO) mice compared with the skin of wild-type mice. UV-induced activation of nuclear factor-kappaB (NF-kappaB)/p65 in the skin of IL-12 KO mice was also more prominent. The levels of NF-kappaB-targeted proteins, such as proliferating cell nuclear antigen (PCNA), cyclooxygenase-2, cyclin D1, and inducible nitric oxide synthase, were higher in the UV-exposed skin of IL-12 KO mice than the UV-exposed skin of wild types. In short-term UV irradiation experiments, subcutaneous treatment of IL-12 KO mice with recombinant IL-12 (rIL-12) or topical treatment with oridonin, an inhibitor of NF-kappaB, resulted in the inhibition of UV-induced increases in the levels of PCNA, cyclin D1, and NF-kappaB compared with non-rIL-12- or non-oridonin-treated IL-12 KO mice. UV-induced skin tumors of IL-12 KO mice had higher levels of PI3K, p-Akt (Ser(473)), p-ERK1/2, p-p38, NF-kappaB, and PCNA and fewer apoptotic cells than skin tumors of wild types. Together, these data suggest that the loss of endogenous IL-12 activates survival signals in UV-exposed skin and that may lead to the enhanced photocarcinogenesis in mice.
Meeran
Syed M
SM
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Katiyar
Nandan
N
Singh
Tripti
T
Katiyar
Santosh K
SK
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000528:radiation effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D018664:Interleukin-12 / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D019938:Cyclin D1; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases