Mitogen-activated protein kinases facilitate many cellular processes and are essential for immune cell function. Their activity is controlled by kinases and dual-specificity phosphatases. A comprehensive microarray analysis of human leukocytes identified DUSP2 (encoding the phosphatase PAC-1) as one of the most highly induced transcripts in activated immune cells. We generated Dusp2(-/-) mice and found considerably reduced inflammatory responses in the 'K/BxN' model of rheumatoid arthritis. PAC-1 deficiency led to increased activity of Jun kinase (Jnk) but unexpected impairment of the activity of extracellular signal-regulated kinase (Erk) and the kinase p38, reduced activity of the transcription factor Elk1 and a complex of mobilized transcription factor NFAT and the AP-1 transcription factor and decreased effector immune cell function. Thus, PAC-1 is a key positive regulator of inflammatory cell signaling and effector functions, mediated through Jnk and Erk mitogen-activated protein kinase crosstalk.

Partial hepatectomy (PH) triggers a rapid regenerative response in the remaining tissue to reinstate the organ function and the cell numbers. Among the molecules that change in the course of regeneration is an accumulation of prostaglandin E2 in the sera of rats with PH. Analysis of the cyclooxygenase (COX) isoenzymes in the remnant liver showed the preferential expression of COX-2 in hepatocytes. Cultured regenerating hepatocytes expressed significant levels of COX-2, a process that was not observed in the sham counterparts. Maximal expression of COX-2 was detected 16 h after PH with increased levels present even at 96 h. Pharmacological inhibition of COX-2 activity with NS398 shunted the up-regulation of cell proliferation after PH, which suggests a positive interaction of prostaglandins with the progression of the cell cycle. Similar results were obtained after PH of mice lacking the COX-2 gene. The expression of COX-2 in regenerating liver was concomitant with a decrease in CCAAT-enhancer binding protein (C/EBP-a) level and an increase in the expression of C/EBP-b and C/EBP-d. These results suggest a contribution of the enhanced synthesis of prostaglandins to liver regeneration observed after PH.

Treatment of primary cultures of fetal hepatocytes with proinflammatory cytokines, lipopolysaccharide (LPS), and hepatocyte growth factor promoted the expression of cyclooxygenase-2 (COX-2) and the synthesis of high amounts of prostaglandins (PGs). Under these conditions, the active forms of the matrix metalloproteinases-2 and -9 (MMPs) were released to the extracellular medium. This process was inhibited when the synthesis of PGs was suppressed pharmacologically with COX-2 inhibitors. Addition to the cell cultures of PGE 2 promoted the release of MMPs through a mechanism that involved the expression of COX-2 and the synthesis of additional PGs. Kinetic analysis of the secretion of MMPs in response to LPS and PGE 2 showed a similar time course, with a lag period of 6 hours, which suggests that PGE 2 does not act directly on the mechanism of MMP processing and release. Inhibitors of protein kinase A, p38 MAP kinase, phosphatidylinositol-3-kinase, and nuclear factor B Prostaglandin H synthase, also known as cyclooxygenase (COX), catalyzes the synthesis of prostaglandin H 2 from arachidonate and constitutes a key regulatory step in the biosynthesis of prostanoids. 1-3 Two distinct isoforms of COX are known: COX-1 and COX-2. The two isoenzymes are encoded by different genes, and the control of their expression, regulation of enzyme activity, and physiologic functions are very different. 1,4 COX-1 seems to be involved in the house keeping function of prostaglandins (PGs) 4 and is expressed constitutively. In contrast, COX-2 is inducible, is expressed as an immediate early gene, and is involved in the onset of inflammation and mitogenic responses. 1,3,5,6 COX-2 expression is positively regulated by lipopolysaccharide (LPS), interleukin 1␤, tumor necrosis factor ␣, and reactive oxygen intermediates in different cells. 7,8 In addition to these stimuli, it has been described that hepatocyte growth factor (HGF) and epidermal growth factor (EGF) triggered the expression of COX-2 in rat gastric epithelial cells, in human amnion-derived WISH cells, and in human gingival fibroblasts, and this effect was mediated through the activation of the ERK2 signaling pathway. [9][10][11] Our previous results showed that adult hepatocytes failed to express COX-2 regardless of the proinflammatory factors used. However, fetal hepatocytes, which exhibit a liver phenotype distinct from the adult counterpart, were able to express COX-2 upon challenge with LPS and proinflammatory cytokines. 8 Regarding the mechanism responsible for the suppression of COX-2 inducibility in adult hepatocytes, our data suggest the existence of a close relationship between COX-2 induction and the decrease of C/EBP␣ levels that bind to the nuclear factor-interleukin 6 site of the COX-2 promoter. 12 In addition to inflammation and cell growth regulation, COX-2 expression has been associated with carcinogenesis and tumor development. 3,6 Several population-based studies have detected a 40% to 50% decrease in relative risk for colorectal cancer in persons who regularl...

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