Hydrogen sulfide impairs keratinocyte cell growth and adhesion inhibiting mitogen-activated protein kinase signaling.
The effects of exogenous hydrogen sulfide (H2S) on normal skin-derived immortalized human keratinocytes have been investigated in detail. We show in vitro that exogenous hydrogen sulfide reduces clonal growth, cell proliferation and cell adhesion of human keratinocytes. H(2)S, in fact, decreases the frequency of the putative keratinocyte stem cell subpopulation in culture, consequently affecting clonal growth, and impairs cell proliferation and adhesion of mature cells. As a mechanistic explanation of these effects, we show at the molecular level that (i) H2S reduces the Raf/MAPK kinase/ERK signaling pathway; (ii) the reduced adhesion of sulfur-treated cells is associated to the downregulation of the expression of beta4, alpha2 and alpha6 integrins that are necessary to promote cell adhesion as well as anti-apoptotic and proliferative signaling in normal keratinocytes. One specific interest of the effects of sulfurs on keratinocytes derives from the potential applications of the results, as sulfur is able to penetrate the skin and a sulfur-rich balneotherapy has been known for long to be effective in the treatment of psoriasis. Thus, the relevance of our findings to the pathophysiology of psoriasis was tested in vivo by treating psoriatic lesions with sulfurs at a concentration comparable to that most commonly found in sulfurous natural springs. In agreement with the in vitro observations, the immunohistochemical analysis of patient biopsies showed a specific downregulation of ERK activation levels, the key molecular event in the sulfur-induced effects on keratinocytes.
Gobbi
Giuliana
G
Department of Anatomy, Pharmacology and Forensic Medicine, University of Parma, Parma, Italy.
Ricci
Francesca
F
Malinverno
Chiara
C
Carubbi
Cecilia
C
Pambianco
Maurizia
M
Panfilis
Giuseppe de
Gd
Vitale
Marco
M
Mirandola
Prisco
P
D000368:Aged; D000393:Air Pollutants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003593:Cytoplasm / Q000187:drug effects / Q000201:enzymology; D005434:Flow Cytometry; D006801:Humans; D006862:Hydrogen Sulfide / Q000627:therapeutic use / Q000633:toxicity*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011565:Psoriasis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology
D000393:Air Pollutants; D020929:Mitogen-Activated Protein Kinase Kinases; D001973:Bromodeoxyuridine; D006862:Hydrogen Sulfide