Elevated monocytic IL-12 and TNF-alpha production in Wegener's granulomatosis is normalized by cyclophosphamide and corticosteroid therapy.
Wegener's granulomatosis (WG) is characterized by a predominance of the type 1 T-helper cell (Th1) response. We have studied monocytic cytokine expression in untreated patients and in patients who did not respond to prior methotrexate or trimethoprim-sulphamethoxazole therapy, i.e. patients with active disease. Intracytoplasmic IL-12 and TNF-alpha expression was significantly increased in WG compared with healthy controls. IL-8 expression was not increased. Two and 12 weeks of daily standard oral cyclophosphamide and corticosteroid (CYC + GC) treatment induced a stable remission of the disease. Elevated IL-12 and TNF-alpha expression of monocytes was normalized. The active metabolite of CYC was shown to down-regulate IL-12 mRNA in vitro. Monocytic cytokines, especially IL-12, may have a role in the early determination and skewing of the immunoregulatory response towards a Th1 profile. It appears that CYC + GC exerts its effect by normalizing the Th1-driving cytokine pattern, and CYC may maintain this mode of action. Normalization of the skewed cytokine pattern may be a prerequisite and an indicator of inducing a remission in WG.
Lamprecht
P
P
Department of Rheumatology, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
Kumanovics
G
G
Mueller
A
A
Csernok
E
E
Komocsi
A
A
Trabandt
A
A
Gross
W L
WL
Schnabel
A
A
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000378:metabolism; D007700:Kinetics; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012074:Remission Induction; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000305:Adrenal Cortex Hormones; D016207:Cytokines; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D003520:Cyclophosphamide