SummaryFibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.

Short pulses (∼10 ns) of high-power laser light produce a sudden increase in the surface temperature of a Pt(111) single-crystal electrode in acidified potassium perchlorate or sulfate solutions. The change of the electrode potential at open circuit was monitored during the relaxation of the temperature. At low pH, the potential transients in the hydrogen adsorption region exhibit a bipolar shape, which can be explained considering that the relaxation is influenced by the rate of hydrogen adsorption. With this assumption, we have estimated a value of the rate constant for hydrogen adsorption around 8 × 10 6 M -1 s -1 . By increasing the pH, the rate of hydrogen adsorption is reduced, making it possible to decouple the double-layer response from the hydrogen adsorption process. In this case, the potential where the double-layer response to the temperature increase is zero can be identified with the potential of maximum entropy of formation of the double layer. This potential is located in the double-layer region (ca. 0.43 V vs Pd/H 2 ) for a solution of pH 3. The relevance of this measurement in terms of the location of the potential of zero charge is discussed.

12/15-Lipoxygenase (LOX) mediates immune-regulatory activities not accounted for by its known free acid eicosanoids, suggesting that additional lipids may be generated by activated cells. To characterize novel LOX-derived lipids, a lipidomic approach was utilized. Ionophore-activated interleukin-4-treated human peripheral monocytes generated up to 10-fold more esterified 15-hydroxyeicosatetraenoic acid (15-HETE) than free in a phosphatidylinositol 3-kinase-and protein kinase C-sensitive manner. Precursor scanning electrospray ionization/tandem spectroscopy for m/z 319 (HETE, [M-H] ؊ ) showed 4 ions at m/z 738, 764, 766, and 782 that were identified using tandem spectroscopy and MS3 as specific diacyl and plasmalogen 15-HETE phosphatidylethanolamines. Using H 2 18 O water, the compounds were shown to form by direct oxidation of endogenous phosphatidylethanolamine (PE) by 15-LOX, with PE being the preferred phospholipid pool containing 15-HETE. Similarly, human platelets generated 4 analogous PE lipids that contained 12-HETE and increased significantly in response to ionophore, collagen, or convulxin. These products were retained in the cells, in contrast to free acids, which are primarily secreted. Precursor scanning of platelet extracts for the major platelet-derived prostanoid, thromboxane B2 (m/z 369.2), did not reveal PE esters, indicating that this modification is restricted to the LOX pathway. In summary, we show formation of PE-esterified HETEs in immune cells that may contribute to LOX signaling in inflammation.

5-Lipoxygenase (5-LOX) plays key roles

Interleukin (IL)-6 acts via a receptor complex consisting of the cognate IL-6 receptor (IL-6R) or the soluble IL-6 receptor (sIL-6R) and glycoprotein 130 (gp130).Here, we investigated the role of these IL-6R components in hypertension and vascular hypertrophy in mice. Angiotensin (Ang) II (1.1 mg/kg/day) caused hypertension and cardiac/aortic hypertrophy in wildtype, but not IL-6 ؊/؊ , mice throughout 7 days. A recombinant dimeric soluble gp130 (sgp130Fc; 50 to 100 g, i.p.) blocked Ang II hypertension but not hypertrophy in wild-type mice. Cognate IL-6R was detected in aortic smooth muscle, but its levels and those of plasma sIL-6R were ϳ50% decreased in IL-6 ؊/؊ mice. Ang II infusion activated signal transducer and activator of transcription-3 in heart of WT and decreased Ang II receptor 1 (ATR1) expression in aorta. Both responses were unaffected by sgp130Fc and absent in IL-6 ؊/؊ mice. In summary, we show that IL-6 trans-signaling is required for Ang II-dependent hypertension, but that hypertrophy, down-regulation of AT1R, and cardiac signal transducer and activator of transcription-3 activation are mediated via cognate IL-6R. These data show that IL-6 responses in a single disease context are governed by both modes of IL-6 signaling, with each pathway eliciting different outcomes. Inhibition of IL-6 signaling is suggested as a potential therapy for hypertension and cardiac hypertrophy. There is emerging evidence for a role of interleukin (IL)-6 and its related cytokines in angiotensin (Ang) II-dependent vascular dysfunction. Plasma levels of IL-6 are strongly associated with hypertension in humans and can be decreased by administration of Ang II receptor antagonists.