Effects of drugs and anticytokine antibodies on expression of ATP2A2 and ATP2C1 in cultured normal human keratinocytes.
BACKGROUND
Darier's disease (DD) and Hailey-Hailey disease (HHD) are skin disorders arising, respectively, from autosomal dominant mutations in ATP2A2, encoding the sacro/endoplasmic reticulum calcium ATPase, and ATP2C1, encoding the Golgi apparatus calcium ATPase. Exposure to ultraviolet (UV) B irradiation exacerbates the skin lesions, which can be treated with corticosteroids and retinoids.


OBJECTIVE
To investigate the molecular basis for DD and HHD.


METHODS
We used quantitative reverse transcriptase-polymerase chain reactions to examine the effects of UVB irradiation on ATP2A2 and ATP2C1 mRNA levels in cultured normal keratinocytes.


RESULTS
We observed that UVB irradiation reduced ATP2A2 and ATP2C mRNA levels. The addition of retinoids or corticosteroids to the cell culture inhibited the UVB-induced suppression of both ATP2A2 and ATP2C1 mRNA levels, and UVB-induced suppression of ATP2C1 mRNA was also inhibited by the addition of ciclosporin, tacrolimus and vitamin D(3). The addition of anti-interleukin (IL)-6 antibody to the cell culture prevented the UVB-induced suppression of ATP2A2 and ATP2C1 mRNA; in contrast, the addition of anti-IL-8 antibody slightly accelerated the suppression.


CONCLUSIONS
These results suggest that drugs effective for DD and HHD act by modulating ATP2A2 and ATP2C1 mRNA expression, respectively, and that the proinflammatory cytokines IL-6 and IL-8 play important roles in the regulation of ATPA2 and ATP2C1 expression in homeostasis and/or inflammation of the skin.
Mayuzumi
N
N
Department of Dermatology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. mayu@med.juntendo.ac.jp
Ikeda
S
S
Kawada
H
H
Ogawa
H
H
D000906:Antibodies / Q000276:immunology; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D007644:Darier Disease / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D016506:Pemphigus, Benign Familial / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014212:Tretinoin / Q000494:pharmacology; D014466:Ultraviolet Rays
D000906:Antibodies; D016207:Cytokines; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D014212:Tretinoin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases