Interleukin-12 deficiency is permissive for angiogenesis in UV radiation-induced skin tumors.
We have shown previously that endogenous deficiency of interleukin (IL)-12 promotes photocarcinogenesis in mice. To characterize the role of IL-12 deficiency in tumor angiogenesis, we developed IL-12p35 knockout (IL-12 KO) mice on a C3H/HeN background. IL-12 KO mice and their wild-type (WT) counterparts were subjected to a photocarcinogenesis protocol. When tumor yield was stabilized, samples of tumor and tumor-uninvolved UVB-exposed skin were collected and subjected to immunohistochemistry, gelatinolytic zymography, real-time PCR, and Western blot analysis of angiogenic factors. We found that the protein, mRNA expression and/or activity of the matrix metalloproteinases (MMP)-2, MMP-3, MMP-7, and MMP-9, and basic fibroblast growth factor, which play crucial roles in tumor growth, were significantly higher in UVB-exposed skin and tumors of IL-12 KO mice compared with WT mice. With respect to the tumor vasculature, the expression of CD31-positive cells and the expression of vascular endothelial growth factor were higher in the tumors of IL-12 KO mice than WTs. The proliferative capacity of tumor cells of the IL-12 KO mice was significantly higher than their WT counterparts when determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by analyzing the expression of cyclin D1. The level of the proinflammatory cytokine IL-6 and the expression of IL-23 in tumors of IL-12 KO mice were markedly higher than in the tumors of WT mice. IL-23 has been shown to promote tumor growth. Together, these data indicate for the first time that IL-12 deficiency promotes proangiogenic stimuli in UVB-induced skin tumors and suggest that endogenous enhancement of IL-12 levels may be effective in the prevention and treatment of UV-induced skin cancers.
Meeran
Syed M
SM
Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294, USA.
Katiyar
Suchitra
S
Elmets
Craig A
CA
Katiyar
Santosh K
SK
D000818:Animals; D015153:Blotting, Western; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000172:deficiency*; D053759:Interleukin-23 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000098:blood supply* / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000528:radiation effects; D012878:Skin Neoplasms / Q000098:blood supply* / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D053759:Interleukin-23; D015850:Interleukin-6; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D018664:Interleukin-12; D020782:Matrix Metalloproteinases