title: Macrophage migration inhibitory factor ameliorates UV-induced photokeratitis in mice.
abstract: Acute ultraviolet (UV) exposure causes photokeratitis, and induces apoptosis in corneal cells of the eye. Macrophage migration inhibitory factor (MIF) was originally identified as a lymphokine. Today, MIF is considered as an integral component of the host antimicrobial alarm system and stress response that promotes the proinflammatory functions of immune cells. Also, MIF is considered to contribute the wound healing process. The aim of the present study is to determine the effects of MIF expression on UV irradiated corneal damage. MIF transgenic (MIF-Tg), wild type (WT), and MIF deficient (MIF KO) mice were UVB-irradiated of 400mJ/cm2 to induce acute UV-photokeratitis. MIF Tg mice constitutively produce high levels of MIF. Morphological changes were most severe in MIF KO mice, and WT and MIF Tg mice were following. Corneal basement membrane of MIF-Tg was well preserved. Prominent higher level of MIF was observed in MIF-Tg than WT after UVB irradiation in cornea. TUNEL staining showed a significantly smaller number of TUNEL positive nuclei in MIF-Tgm (6.2+/-4.3 cells/section, p<0.01 compared with WT) than WT (30.7+/-9.1) and MIF KO mice (32.1+/-12.7) 24h after UV exposure. The number of c-Jun positive nuclei was significantly higher in MIF Tg (p<0.01) than in WT and MIF KO mice. Serial observation revealed that BrdU incorporation was significantly upregulated in MIF Tg (p<0.01), but downregulated in MIF KO (p<0.01) than WT mice. MIF expression may thus be related to the amelioration of UVB-caused corneal injury, and this association was attributable to the upregulation of cell proliferation after acute UV-induced corneal damage, which involves the c-Jun dependent pathway. In conclusion, UV-damaged cornea is recoverable without MIF, however it takes longer time than normal condition. Cornea is less damaged and can make a quick recovery when ocular tissue is enough supplied with MIF.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan. nobukita@med.hokudai.ac.jp
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kitaichi
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yoshida
authors.forename: Ayumi
authors.initials: A
authors.lastname: Honda
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yoshihisa
authors.forename: Satoru
authors.initials: S
authors.lastname: Kase
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohgami
authors.forename: Osamu
authors.initials: O
authors.lastname: Norisugi
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Makino
authors.forename: Jun
authors.initials: J
authors.lastname: Nishihira
authors.forename: Sho-Ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ohno
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D019573:Epithelium, Corneal / Q000473:pathology / Q000528:radiation effects; D005136:Eye Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000528:radiation effects; D020287:In Situ Nick-End Labeling; D007634:Keratitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010787:Photosensitivity Disorders / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D005136:Eye Proteins; D008263:Macrophage Migration-Inhibitory Factors; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger