Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate.
Type 2 cytokines are thought to have a protective role in psoriasis vulgaris by dampening the activity of T helper 1 (Th1) lymphocytes. The aim of the present study was to determine the effect of monomethylfumarate (MMF), the most active metabolite of the new anti-psoriatic drug Fumaderm, on the production of cytokines and the development of Th subsets. MMF was found to enhance interleukin (IL)-4 and IL-5 production by CD2/CD8 monoclonal antibody-stimulated peripheral blood mononuclear cells (PBMC) in a dose-dependent manner. Maximal effects of MMF were found at a concentration of 200 microM and resulted in tenfold enhanced levels of IL-4 and IL-5 production. MMF did not affect the levels of IL-2 production, interferon (IFN)-gamma production or proliferative T cell responses in these cultures. Similar effects of MMF were observed in cultures of purified peripheral blood T cells indicating that this compound can act directly on T cells. MMF did not influence cytokine production by purified CD4+CD45RA+ (unprimed) T cells, but greatly enhanced IL-4 and IL-5 production without affecting IFN-gamma production by purified CD4+CD45RO+ (primed) T cells. Furthermore, MMF also augmented IL-4 and IL-5 production in established Th1/Th0 clones that were stimulated with CD2/CD28 monoclonal antibody. Finally, when PBMC were challenged with Mycobacterium tuberculosis that typically induces Th1 recall responses with strong IFN-gamma secretion, MMF again appeared to induce high levels of IL-4 and IL-5 secretion while IFN-gamma production was unaffected. These results may be relevant for the development of therapeutic regimens designed to correct inappropriate Th1 subset development in immunopathologic conditions.
de Jong
R
R
Department of Immunohematology and Bloodbank, University Hospital Leiden, The Netherlands.
Bezemer
A C
AC
Zomerdijk
T P
TP
van de Pouw-Kraan
T
T
Ottenhoff
T H
TH
Nibbering
P H
PH
D000818:Animals; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007156:Immunologic Memory; D015847:Interleukin-4 / Q000096:biosynthesis*; D015848:Interleukin-5 / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D008298:Maleates / Q000494:pharmacology*; D011565:Psoriasis / Q000188:drug therapy*; D012756:Sheep; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
D005650:Fumarates; D015848:Interleukin-5; D008298:Maleates; C073341:citraconic acid; D015847:Interleukin-4; D017493:Leukocyte Common Antigens