Systemic macrophage activation in locally-induced experimental arthritis

Local and systemic macrophage activation was examined during the course of monoarticular murine antigen-induced arthritis (AIA), induced by systemic immunization and subsequent local induction. The levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-12p70, and nitric oxide (NO) were determined in joints, sera, and supernatants of peritoneal macrophages (the latter unstimulated or stimulated ex vivo with LPS/IFN-gamma). In comparison with normal mice, systemic immunization (day 0) was associated to significant rise of TNF-alpha in serum, IL-1beta in the joints, IL-6 in unstimulated macrophages and IL-12p70 in stimulated macrophages. Local induction led to a further significant increase of: (i) TNF-alpha, IL-1beta, and IL-6 in the joints; and (ii) IL-1beta, and IL-6 in sera and stimulated macrophages during acute and/or early chronic AIA (days 1 to 7). Unstimulated macrophages showed increased NO release (day 3), while stimulated macrophages significantly increased secretion of IL-12p70 (day 1). In late chronic AIA (day 21), cytokine/NO expression returned to immunization levels or below at all sites; solely IL-1beta in the joints remained significantly above normal levels. Therefore, the prevalently local AIA model is characterized by a mixture of local and systemic activation of the mononuclear phagocyte system (MPS). While systemic MPS activation preceding arthritis induction can be attributed to systemic immunization, further systemic activation during arthritis appears an integral pathogenetic component of AIA.