Nitric oxide (NO) possesses potent anti-inflammatory properties; however, an over-production of NO will promote inflammation and induce cell and tissue dysfunction. Thus, the ability to precisely regulate NO production could prove beneficial in controlling damage. In this study, advantage was taken of the well characterized inflammatory response caused by an intestinal parasite, Trichinella spiralis, to study the relationship between intestinal inflammation and the regulation of nitric oxide synthase-type 2 (NOS-2) expression. Our study revealed that a specific gut inflammatory reaction results in inhibition of NOS-2 expression. Characteristics of this inhibition are: 1) local jejunal inflammation induced by T. spiralis systemically inhibits NOS-2 gene transcription, protein expression, and enzyme activity; 2) the inhibition blunts endotoxin-stimulated NOS-2 expression; 3) the inhibition does not extend to the expression of other isoforms of NOS, to paxillin, a housekeeper protein, or to cyclooxygenase-2, another protein induced by proinflammatory cytokines; 4) the inhibition is unlikely related to the formation of specific anti-parasite antibodies; and 5) the inhibition may involve substances other than stress-induced corticosteroids. Elucidation of such potent endogenous NOS-2 down-regulatory mechanisms could lead to the development of new strategies for the therapy of inflammatory conditions characterized by the overproduction of NO.

Gastrointestinal nematode infection is known to alter host T cell activation and has been used to study immune and inflammatory reactions in which nitric oxide (NO) is a versatile player. We previously demonstrated that Trichinella spiralis infection inhibits host inducible NO synthase (NOS-2) expression. We now demonstrate that (i) an IL-4 receptor ␣-subunit (IL-4R␣)͞Stat6-dependent but T cell-independent pathway is the key for the nematodeinduced host NOS-2 inhibition; (ii) endogenous IL-4 and IL-13, the only known IL-4R␣ ligands, are not required for activating the pathway; and (iii) treatment of RAW264.7 cells with parasitecultured medium inhibits NOS-2 expression but not cyclooxygenase 2 expression. We propose that a yet-unidentified substance is released by the nematode during the host-parasite interaction.inflammation ͉ nematode ͉ immunoregulation ͉ nitric oxide ͉ endotoxin G astrointestinal nematode infection has served as a well established model to study parasite-induced host T cell activation and cytokine regulation (1, 2). Interaction within the cytokine network plays a key role in the control of immunity and inf lammation that mediates host protective responses (3, 4). Recently, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system based on several findings. (i) Producing or responding to NO is a major feature of macrophages and many other immunesystem cells. (ii) All isoforms of NO synthase (NOS) are expressed in the immune system, and induction of inducible NOS (NOS-2) has been implicated in a variety of immunologic inf lammatory conditions. (iii) NOS-2 expression is upregulated by T helper 1 (Th1) cytokines and inhibited by Th2 cytokines. In addition, the effects of NO are not restricted to any single cytokine receptor. Thus, NO plays a very diverse role in the immune system. (iv) Activation of NOS-2 results in the production of a high concentration of NO. Highly diffusible ⅐ NO is rapidly oxidized to reactive nitrogen species that are detrimental in several immunopathologic processes [see reviews (5-7) for further information].We have previously demonstrated that Trichinella spiralis infection induces down-regulation of NOS-2 expression (8), which has the following characteristics. (i) Local jejunal infection by T. spiralis systemically inhibits NOS-2 gene transcription, protein expression, and enzyme activity in the ileum, jejunum, colon, kidney, lung, and uterus. (ii) The effect of inhibition is potent and can override endotoxin-induced NOS-2 expression. (iii) The inhibition does not extend to the expression of other isoforms of NOS; to paxillin, a housekeeper protein; or to cyclooxygenase 2 (COX-2), another protein induced by proinflammatory cytokines. (iv) The inhibition is not associated with a chemically induced intestinal inflammatory response. (v) The inhibition is unlikely related to the formation of specific antiparasite antibodies. (vi) The inhibition may involve substances other than stress-induced corticosteroids.The objective of the current...

Infection with Trichinella spiralis in the rat causes altered intestinal motility and jejunal smooth muscle contractility by day 6 postinoculation. The purpose of this study was to determine structural and molecular changes in the smooth muscle that could account for the functional changes that have been reported. By day 6 postinoculation, there was an increase in thickness of both muscle layers of the jejunum. This increase in mass was accompanied by an increase in total protein content of the seromuscular tissues. When specific proteins were analyzed, increases in actin and myosin heavy chain contents were found. On the other hand, there was no increase in collagen content. Alterations in gene expression at the pretranslational level were determined by monitoring total RNA and the proportion of mRNA that codes for alpha-smooth muscle actin. There was an increase in both parameters in longitudinal muscle from the jejunum of infected animals. The increase appeared to be site selective because there were no increases in either parameter in longitudinal muscle of the distal intestine. These results indicate that pretranslational upregulation of gene expression for actin isoforms occurs in smooth muscle of the proximal but not distal intestine during the early enteric phase of infection with T. spiralis. Thus the altered smooth muscle contractility that has been reported in experimental trichinosis may be related in part to an increased expression of smooth muscle protein.

A diet of 1% beta-guanidinopropionic acid (beta-GPA) fed to rats for weeks results in decreased muscle adenosine triphosphate and creatine phosphate concentrations (J. Biol. Chem. 249: 1060-1063, 1974), increased activities of selected mitochondrial enzymes (Biochem. J. 232: 125-131, 1985), and atrophied type IIb fibers (Lab. Invest. 33: 151-158, 1975). The hypothesis of the present study was that chronic beta-GPA feeding would increase cytochrome c mRNA in muscle and would decrease alpha-skeletal actin mRNA in type IIb muscle. Data collected supported, in part, the hypothesis. After 22 days of a 1% beta-GPA diet, cytochrome c mRNA was increased 60-67% in muscles with inherently low cytochrome c mRNA but was not altered in muscles with higher cytochrome c mRNA levels. alpha-Skeletal actin mRNA was unchanged in muscles with low and high cytochrome c mRNA after 22 days of 1% beta-GPA. After 66 days of beta-GPA feeding, both cytochrome c mRNA and alpha-skeletal actin mRNA were decreased 18 and 26%, respectively, per unit of total RNA, in white quadriceps muscle. At the same time muscles composed of predominantly type II fibers atrophied 22%, whereas type I muscle size was unaltered. These data suggest that high-energy phosphate levels could play some role in adaptive changes in muscle composition.

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