The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells.
BACKGROUND
The effectiveness of systemic treatment of psoriasis with fumaric acid esters has been proven, but their mode of action at the cellular and molecular level has not yet been fully elucidated.


OBJECTIVE
To study the effect of dimethylfumarate (DMF) on the production of the chemokines CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11, formerly known as GROalpha, interleukin-8, Mig, IP-10 and IP-9/I-TAC, respectively, in human keratinocytes and peripheral blood mononuclear cells (PBMC).


METHODS
Cultured keratinocytes were stimulated with interferon (IFN) -gamma to produce CXCL9, CXCL10 and CXCL11 and with phorbol myristate acetate to produce CXCL1 and CXCL8 in the absence and presence of DMF (5, 15 and 45 micromol L(-1)). PBMC were stimulated with either IFN-gamma to produce CXCL9 and CXCL10 or lipopolysaccharide to produce CXCL8, in the absence and presence of DMF (5, 15 and 45 micromol L(-1)). RNA preparations from isolated keratinocytes were analysed by Northern blotting; protein production by keratinocytes and PBMC was monitored by an enzyme-linked immunosorbent assay.


RESULTS
Northern blot analysis on isolated keratinocyte RNA preparations showed a dose-dependent inhibition of CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11 transcription by DMF. At 45 micromol L(-1) the inhibition was almost complete. In addition, keratinocytes and PBMC showed in the presence of DMF a dose-dependent inhibition of CXCL8, CXCL9 and CXCL10 protein production.


CONCLUSIONS
These results show the ability of DMF to inhibit the production of chemokines that may be critically involved in the development and perpetuation of psoriatic lesions. This might explain, at least in part, the beneficial effects of treatment with fumaric acid esters in psoriasis patients.
Stoof
T J
TJ
Department of Dermatology, University Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Flier
J
J
Sampat
S
S
Nieboer
C
C
Tensen
C P
CP
Boorsma
D M
DM
D015152:Blotting, Northern; D018929:Cell Culture Techniques; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D003879:Dermatologic Agents / Q000494:pharmacology*; D000069462:Dimethyl Fumarate; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy; D012333:RNA, Messenger / Q000235:genetics
D019743:Chemokines, CXC; D003879:Dermatologic Agents; D005650:Fumarates; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D000069462:Dimethyl Fumarate