Heme oxygenase-1 inhibits T cell-dependent skin inflammation and differentiation and function of antigen-presenting cells.
Heme oxygenase-1 (HO-1) is increased in psoriatic skin. We asked for the impact of physiological and pharmacological HO-1 induction on skin immunity and the mechanisms involved in HO-1-induced immunomodulation. We found cutaneous HO-1 expression upregulated comparable with suppressors of cytokine signalling (SOCS)1 and SOCS3 in psoriasis and atopic eczema and temporarily increased in murine ovalbumin-induced late phase reaction (LPR) and 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). Cutaneous inflammation was enhanced by HO-1 inhibition and was abrogated by treatment with the HO-1 inducer cobaltic protoporphyrin (CoPP) both when applied around sensitization or before challenge. HO-1 inhibition specifically prevented the anti-inflammatory CoPP effect. CoPP inhibited T cell proliferation in splenocytes of treated mice and in human mixed leukocyte reaction and lymphocyte transformation test. CoPP induced HO-1 in antigen-presenting cells and depressed monocytic accessory molecule expression and the differentiation and maturation of monocyte-derived dendritic cells (MDDC). It decreased tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 production while increasing IL-10 secretion. The antigen-presenting capacity was diminished in CoPP-treated and HO-1-transduced MDDC. We demonstrate for the first time the physiological role of HO-1 in the limitation of skin inflammation and implement pharmacological HO-1 induction as a therapeutic approach for T cell-dependent inflammatory dermatoses. Suppression of antigen-presenting cells may represent a main anti-inflammatory mechanism of HO-1.
Listopad
Joanna
J
TRG Inflammation & Immunology, Bayer Schering Pharma AG, D-13442 Berlin, Germany.
Asadullah
Khusru
K
Sievers
Claudia
C
Ritter
Thomas
T
Meisel
Christian
C
Sabat
Robert
R
Döcke
Wolf-Dietrich
WD
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003035:Cobalt / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D003872:Dermatitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016130:Immunophenotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
D011524:Protoporphyrins; D003035:Cobalt; D051547:Heme Oxygenase-1