A critical role for leukotriene B₄ in K/BxN serum transfer arthritis pathogenesis

The leukotrienes (LTs) are potent inflammatory mediators whose functions include modulation of vascular permeability, induction of adhesion molecule expression, potent leukocyte chemoattraction, stimulation of smooth muscle contraction, induction of synovial fibroblast proliferation and triggering of cytokine secretion. Knowing that these bioactivities are active in the context of inflammatory arthritis, we hypothesized that the LTs may play a critical role in the pathogenesis of murine K/BxN serum transfer arthritis. We used a genetic approach to demonstrate the functional requirement for specific LT species in the induction of K/BxN serum transfer arthritis. We find that mice lacking 5-lipoxygenase, a proximal enzyme in LT biosynthesis, are resistant to the development of arthritis. We further demonstrate that LTA₄ hydrolase-deficient mice, specifically lacking LTB₄, are also profoundly resistant to arthritis induction. In contrast, mice lacking LTC₄ synthase (and thus lacking all cysteinyl LTs), are fully competent to develop arthritis. The profound requirement for LTB₄ highlights the importance of this lipid mediator of inflammation in the orchestrated, yet poorly understood, process of arthritis. Furthermore, these observations provide an in vivo rationale for pursuit of therapies directed at LTs and their receptors, an inflammatory pathway not currently utilized in treatment of patients with inflammatory arthritis.