Elevated monocytic IL-12 and TNF-αproduction in Wegener's granulomatosis is normalized by cyclophosphamide and corticosteroid therapy

Abstract

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‐α 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‐α 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.