Functional Significance of MMP-9 in Tumor Necrosis Factor-Induced Proliferation and Branching Morphogenesis of Mammary Epithelial Cells*

Keratin 8 and 18 (K8/18) are the major components of intermediate filament (IF) proteins of simple or single-layered epithelia. Recent data show that normal and malignant epithelial cells deficient in K8/18 are nearly 100 times more sensitive to tumor necrosis factor (TNF)–induced cell death. We have now identified human TNF receptor type 1 (TNFR1)–associated death domain protein (TRADD) to be the K18-interacting protein. Among IF proteins tested in two-hybrid systems, TRADD specifically bound K18 and K14, type I (acidic) keratins. The COOH-terminal region of TRADD interacted with the coil Ia of the rod domain of K18. Endogenous TRADD coimmunoprecipitated with K18, and colocalized with K8/18 filaments in human mammary epithelial cells. Overexpression of the NH2 terminus (amino acids 1–270) of K18 containing the TRADD-binding domain as well as overexpression of K8/18 in SW13 cells, which are devoid of keratins, rendered the cells more resistant to killing by TNF. We also showed that overexpressed NH2 termini of K18 and K8/18 were associated with endogenous TRADD in SW13 cells, resulting in the inhibition of caspase-8 activation. These results indicate that K18 may sequester TRADD to attenuate interactions between TRADD and activated TNFR1 and moderate TNF-induced apoptosis in simple epithelial cells.

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Tumor necrosis factor alpha induces LIF expression through ERK1/2 activation in mammary epithelial cells

Journal of Cellular Biochemistry ◽

10.1002/jcb.22595 ◽

2010 ◽

Vol 110 (4) ◽

pp. 857-865 ◽

Cited By ~ 16

Author(s):

Carolina Schere Levy ◽

Victoria Slomiansky ◽

Albana Gattelli ◽

Karen Nahmod ◽

Federico Pelisch ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Epithelial Cells ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

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Comparative Kinetics ofEscherichia coli- andStaphylococcus aureus-Specific Activation of Key Immune Pathways in Mammary Epithelial Cells Demonstrates ThatS. aureusElicits a Delayed Response Dominated by Interleukin-6 (IL-6) but Not by IL-1A or Tumor Necrosis Factor Alpha

Infection and Immunity ◽

10.1128/iai.01071-10 ◽

2010 ◽

Vol 79 (2) ◽

pp. 695-707 ◽

Cited By ~ 101

Author(s):

Juliane Günther ◽

Kathrin Esch ◽

Norbert Poschadel ◽

Wolfram Petzl ◽

Holm Zerbe ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Necrosis Factor Alpha ◽

E Coli ◽

Tnf Α ◽

Factor Alpha ◽

Necrosis Factor

ABSTRACTInfections of the udder byEscherichia colivery often elicit acute inflammation, whileStaphylococcus aureusinfections tend to cause mild, subclinical inflammation and persistent infections. The molecular causes underlying the different disease patterns are poorly understood. We therefore profiled the kinetics and extents of global changes in the transcriptome of primary bovine mammary epithelial cells (MEC) after challenging them with heat-inactivated preparations ofE. coliorS. aureuspathogens.E. coliswiftly and strongly induced an expression of cytokines and bactericidal factors.S. aureuselicited a retarded response and failed to quickly induce an expression of bactericidal factors. Both pathogens induced similar patterns of chemokines for cell recruitment into the udder, butE. colistimulated their synthesis much faster and stronger. The genes that are exclusively and most strongly upregulated byE. colimay be clustered into a regulatory network with tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) in a central position. In contrast, the expression of these master cytokines is barely regulated byS. aureus. Both pathogens quickly trigger an enhanced expression of IL-6. This is still possible after completely abrogating MyD88-dependent Toll-like receptor (TLR) signaling in MEC. TheE. coli-specific strong induction of TNF-α and IL-1 expression may be causative for the severe inflammatory symptoms of animals suffering fromE. colimastitis, while the avoidance to quickly induce the synthesis of bactericidal factors may support the persistent survival ofS. aureuswithin the udder. We suggest thatS. aureussubverts the MyD88-dependent activation of immune gene expression in MEC.

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