NF-kappaB family of transcription factors plays a pivotal role in regulation of immune and inflammatory responses. NF-kappaB is known to function by binding to the kappaB enhancer and directly activating target gene transcription. Here we demonstrate another function of NF-kappaB, in which the nfkappab1 gene product p105 regulates MAP kinase signaling triggered by the bacterial component lipopolysaccharide. p105 exerts this signaling function by controlling the stability and function of an upstream kinase, Tpl2. In macrophages, Tpl2 forms a stable and inactive complex with p105, and activation of Tpl2 involves its dissociation from p105 and subsequent degradation. Thus, p105 functions as a physiological partner and inhibitor of Tpl2, which provides an example of how a transcription factor component regulates upstream signaling events.

Meprins are metalloendopeptidases expressed by leukocytes in the lamina propria of the human inflamed bowel, that degrade extracellular matrix proteins in vitro implicating them in leukocyte transmigration events. The aims of these studies were to 1) examine the expression of meprins in the mouse mesenteric lymph node, 2) determine whether macrophages express meprins, and 3) determine whether deletion of the meprin β gene (Mep-1β) mitigated the ability of leukocytes to disseminate through extracellular matrix in vitro. These studies show that meprin α and β are expressed in leukocytes of the mouse mesenteric lymph node, and meprin α, but not β, decreased during intestinal inflammation. Deletion of Mep-1β gene decreased the ability of leukocytes to migrate through matrigel compared with wild-type leukocytes. Meprin β, but not α, was detected in cortical and medullary macrophages of the lymph node. Thus overall, meprin β is expressed by leukocytes in the draining lymph node of the intestine, regardless of the inflammatory status of the animal, and is likely to contribute to leukocyte transmigration events important to intestinal immune responses. Thus, the expression of meprins by leukocytes of the intestinal immune system may have important implications for diseases such as inflammatory bowel diseases, which are aggravated by leukocyte infiltration.

Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes and in leukocytes and certain cancer cells. Mature meprins are oligomers of evolutionarily related, separately encoded ␣ and/or ␤ subunits. Homooligomers of meprin ␣ are secreted; oligomers containing meprin ␤ are plasma membrane associated. Meprin substrates include bioactive peptides and extracellular matrix proteins. Meprins have been implicated in cancer and intestinal inflammation. Additionally, meprin ␤ is a candidate gene for diabetic nephropathy. To elucidate in vivo functions of these metalloproteases, meprin ␤ null mice were generated by targeted disruption of the meprin ␤ gene on mouse chromosome 18q12. Analyses of meprin ␤ knockout mice indicated that (i) 50% fewer null mice are born than the Mendelian distribution predicts, (ii) null mice that survive develop normally and are viable and fertile, (iii) meprin ␤ knockout mice lack membrane-associated meprin ␣ in kidney and intestine, and (iv) null mice have changes in renal gene expression profiles compared to wild-type mice as assessed by microarray analyses. Thus, disruption of the meprin ␤ allele in mice affects embryonic viability, birth weight, renal gene expression profiles, and the distribution of meprin ␣ in kidney and intestine.Meprins (meprin A [EC 3.4.24.18] and meprin B [EC 3.4.24.63]), metalloproteases of the astacin family, comprise approximately 5% of kidney brush border membrane protein in mice (2, 3). They are also expressed in intestinal brush border membranes, in leukocytes, and in certain epithelial cancer cells (17,21). Various growth factors, cytokines, and extracellular matrix proteins are substrates for meprin in vitro; among the best substrates are gastrin, gastrin-releasing peptide, monocyte chemoattractant protein-1, osteopontin, and laminin (1, 15). The nature of these substrates and the expression patterns of the subunits in acute renal failure, intestinal disease, and cancerous cells implicate meprins in the regulation of growth, inflammation, cancer cell metastasis, and matrix remodeling (5,15,17,18,21,33).The meprin subunits, ␣ and ␤, associate to form homo-or heterooligomers (19). Although the subunits are encoded by distinct genes on different chromosomes (Mep1␣ on chromosome 6 in humans and 17 in mice and Mep1␤ on chromosome 18 in both species), under some circumstances there is coordinate regulation of the expression of the genes that results in heterooligomeric protein complexes (4). Meprin ␣ and ␤ subunits are 42% identical at the amino acid level and share the same domain structure, except that meprin ␣ contains an inserted (I) domain which is not present in meprin ␤ (20). The I domain directs the proteolytic cleavage of meprin ␣ during maturation in the endoplasmic reticulum so that the bulk of the subunit is released from the membrane. The consequence of the cleavage is that meprin ␣ is secreted unless it interacts with membrane-associated meprin ␤. In vivo, meprin ␣ is secreted as ...