We utilized a line of transgenic mice expressing Photinus luciferase complementary DNA (cDNA) under the control of a nuclear factor kappa B (NF-kappaB)-dependent promoter (from the 5' human immunodeficiency virus-1 [HIV-1] long terminal repeat) to examine the role of NF-kappaB activation in the pathogenesis of systemic inflammation induced by bacterial endotoxin (lipopolysaccharide [LPS]). After intraperitoneal injection of E. coli LPS, these mice displayed a time- and dose-dependent, organ-specific pattern of luciferase expression, showing that NF-kappaB-dependent gene transcription is transiently activated in multiple organs by systemic LPS administration. Luciferase expression in liver could be specifically blocked by intravenous administration of replication-deficient adenoviral vectors expressing a dominant inhibitor of NF-kappaB (IkappaB-alphaDN), confirming that luciferase gene expression is a surrogate marker for NF-kappaB activation in this line of mice. After treatment with intraperitoneal LPS, the mice were found to have increased lung tissue messenger RNA (mRNA) expression of a variety of cytokines that are thought to be NF-kappaB-dependent, as well as elevated serum concentrations of presumed NF-kappaB-dependent cytokines. In lung tissue homogenates, a close correlation was identified between luciferase activity and KC levels. These studies show that systemic treatment with LPS orchestrates a multiorgan NF-kappaB-dependent response that likely regulates the pathobiology of systemic inflammation.

The nuclear factor-B (NF-B) family of transcription factors has been shown to regulate proliferation in several cell types. Although recent studies have demonstrated aberrant expression or activity of NF-B in human breast cancer cell lines and tumors, little is known regarding the precise role of NF-B in normal proliferation and development of the mammary epithelium. We investigated the function of NF-B during murine early postnatal mammary gland development by observing the consequences of increased NF-B activity in mouse mammary epithelium lacking the gene encoding IB␣, a major inhibitor of NF-B. Mammary tissue containing epithelium from inhibitor B␣ (IB␣)-deficient female donors was transplanted into the gland-free mammary stroma of wild-type mice, resulting in an increase in lateral ductal branching and pervasive intraductal hyperplasia. A two-to threefold increase in epithelial cell number was observed in IB␣-deficient epithelium compared with controls. Epithelial cell proliferation was strikingly increased in IB␣-deficient epithelium, and no alteration in apoptosis was detected. The extracellular matrix adjacent to IB␣-deficient epithelium was reduced. Consistent with in vivo data, a fourfold increase in epithelial branching was also observed in purified IB␣-deficient primary epithelial cells in three-dimensional culture. These data demonstrate that NF-B positively regulates mammary epithelial proliferation, branching, and functions in maintenance of normal epithelial architecture during early postnatal development. INTRODUCTIONThe mammary gland is an organ designed to deliver nourishment and passive immunity to infant mammals. It consists of an epithelium that synthesizes and secretes lipid and milk proteins, as well as a fatty stroma that provides support and local growth regulatory cues to the epithelium (reviewed by Medina, 1996). Although the mammary gland rudiment is established during embryogenesis, the majority of mammary gland development occurs postnatally. During puberty, the epithelium proliferates and branches in response to hormonal signals, eventually extending throughout the entire stroma. More extensive growth and differentiation of the epithelium occurs during each round of pregnancy. The distal tips of each epithelial branch proliferate and differentiate into lobuloalveoli, which synthesize and secrete milk during lactation. Upon cessation of nursing, the majority of the epithelium undergoes apoptosis in a process called involution (reviewed by Furth, 1999). After involution, the epithelium remains relatively quiescent until the next pregnancy, when the morphogenetic cycle is repeated.The nuclear factor-B (NF-B) family of transcription factors regulates growth, differentiation, and apoptosis in several tissues, including lymphocytes, embryonic limb, lung and liver, skin, and bone (Beg et al., 1995;Klement et al., 1996;Boothby et al., 1997;Franzoso et al., 1997;Bushdid et al., 1998;Kanegae et al., 1998;Seitz et al., 1998;Bendall et al., 1999;Hu et al., 1999; Li et al., 1999a,b,c;Takeda et...

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