Expression and function of macrophage migration inhibitory factor in the pathogenesis of UV-induced cutaneous nonmelanoma skin cancer.
Chronic skin exposure to ultraviolet light stimulates the production of cytokines known to be involved in the initiation of skin cancer. Recent studies in mouse models suggested a role for macrophage migration inhibitory factor (MIF) in the UVB-induced pathogenesis of nonmelanoma skin cancer (NMSC). Our studies aimed at defining the pathophysiological function of MIF in cutaneous inflammatory reactions and in the development and progression of NMSC. Immunohistochemical analysis revealed a moderate expression of MIF in normal human skin samples but an enhanced expression of this cytokine in lesional skin of patients with actinic keratosis or cutaneous SCC. Enzyme-linked immunosorbent assay studies showed a time-dependent increase in MIF secretion after a moderate single-dose UVB irradiation in NHEKs and SCC tumor cells. MIF is known to interact with CXCR2, CXCR4 and CD74. These receptors are not constitutively expressed in keratinocytes and HaCaT cells and their expression is not induced by UVB irradiation either. However, stimulation with IFNγ upregulated CD74 surface expression in these cells. Affymetrix(®)  Gene Chip analysis revealed that only keratinocytes prestimulated with IFNγ are responsive to MIF. These findings indicate that MIF may be an important factor in the pathogenesis of NMSC tumorigenesis and progression in an inflammatory environment.
Department of Dermatology and Allergology, RWTH Aachen University, Aachen, Germany.
Ruth
R
Heise
Claudia S
CS
Vetter-Kauczok
Claudia
C
Skazik
Katharina
K
Czaja
Yvonne
Y
Marquardt
Hongqi
H
Lue
Hans F
HF
Merk
Jürgen
J
Bernhagen
Jens M
JM
Baron
D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D055623:Keratosis, Actinic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014466:Ultraviolet Rays
D000944:Antigens, Differentiation, B-Lymphocyte; C527276:CXCR4 protein, human; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; C045084:invariant chain; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human