Expression of nuclear factor kappaB and tumor necrosis factor alpha in the mouse brain after experimental thermal ablation injury.

Abstract

Nuclear factor kappa B (NFkappaB) participates in the regulation of a diverse range of genes involved in inflammation and acute phase responses. We investigated the expression of the activated form of NFkappaB and tumor necrosis factor alpha (TNFalpha), an inflammatory cytokine, in experimental brain injury. We generated focal brain injury in mice using radiofrequency thermal ablation at the caudate putamen in mice. Intracerebral expression of TNFalpha and the p50 and p65 subunits of NFkappaB were studied using immunohistochemistry at 1, 4, and 8 hours and at 1, 2, 4, 8, 14, and 28 days postinjury. Coagulative necrosis approximately 2 mm in diameter was produced at the site of injury. No immunoreactivity for TNFalpha, NFkappaB p50, or NFkappaB p65 was detected in the injured area in the early phase postinjury. On posttrauma Day 2, however, weak expression of TNFalpha, NFkappaB p50, and NFkappaB p65 was detected in mononuclear cells that infiltrated edematous tissue surrounding the lesion. On posttrauma Days 4 to 8, the expression of TNFalpha, NFkappaB p50, and NFkappaB p65 was prominently increased in infiltrating and proliferating mononuclear cells (macrophages and microglia) and in proliferating reactive astrocytes surrounding the lesion. Nuclear subcellular localization of the expression of NFkappaB p50 and p65 was observed, which indicated that these subunits might be activated in these cells. On posttrauma Day 14, the expression of TNFalpha, NFkappaB p50, and NFkappaB p65 decreased and was limited to mononuclear cells, and it finally disappeared on Day 28. The temporal profiles of TNFalpha, NFkappaB p50, and NFkappaB p65 were closely associated with the occurrence of secondary insults and the tissue-remodeling process in wound healing. These results suggest that TNFalpha, NFkappaB p50, and NFkappaB p65 may play a central role in the injury-induced immune response that leads to secondary insults or wound healing after brain injury. Inappropriate and deregulated activation of NFkappaB in injured brain tissue may be implicated in the development of secondary brain damage.