NF-KAPPA-B ACTIVATION DURING IGG IMMUNE COMPLEX-INDUCED LUNG INJURY -REQUIREMENTS FOR TNF-ALPHA AND IL-1-BETA BUT NOT COMPLEMENT

The development of acute lung inflammatory injury induced by alveolar deposition of IgG immune complexes in rats requires increased producti on of the proinflammatory cytokines, tumor necrosis factor-cu (TNF-alp ha), and interleukin-1 beta (IL-1 beta) as well as the complement acti vation product, C5a, Transcription of TNF-alpha and IL-1 beta genes ar e known to be regulated by the nuclear factor-kappa B (NF-kappa B), Du ring IgG immune complex-induced lung inflammation, NF-kappa B has been shown to be activated in both alveolar macrophages and whole lung tis sues. In the current studies we sought to determine whether TNF-alpha, IL-1 beta, the complement system and oxidants contribute to the activ ation of NF-kappa B in the lung. Electrophoretic mobility shift analys is of nuclear extracts from whole lung tissues demonstrated that IF-ka ppa B activation induced by the presence of IgG immune complexes occur red independently of the complement st-stem and neutrophils, lntrapulm onary instillation of TNF-alpha or IL-1 beta into normal lung induced NF-kappa B, whereas C5a was incapable of causing NF-kappa B activation . In alveolar macrophages stimulated in vitro with IgG immune complex es, NF-kappa B activation was greatly attenuated in the presence of an tibodies to TNF-alpha or IL-1 beta, Similarly, in vivo blockade of TNF -alpha or IL-1 beta suppressed lung NF-kappa B activation during IgG i mmune complex-induced lung injury. N-acetylcysteine, but not catalase, suppressed activation of lung NF-kappa B. These data suggest that TNF -alpha and IL-1 beta function in an autocrine or paracrine manner to a mplify the lung inflammatory response through activation of NF-kappa B . Oxidants not derived from neutrophils also appear to play a role in this process, whereas complement activation products are not if involv ed in this phenomenon.