Proinflammatory Cytokine Messenger RNA Research Articles

Detrimental Effects of an Inhaled Phosphodiesterase-4 Inhibitor on Lung Inflammation in Ventilated Preterm Lambs Exposed to Chorioamnionitis Are Dose Dependent.

Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 μg/kg) or low dose (1 μg/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.

Chemoprevention of inflammation-related colorectal cancer by silymarin-, acetyl-11-keto-beta-boswellic acid-, curcumin- and maltodextrin-enriched dietetic formulation in animal model.

On the basis of preliminary in vitro experience, we assessed whether an enriched nutritional formulation with estrogen receptor (ER)-beta agonist and anti-inflammatory properties may prevent inflammation-associated colorectal cancer (CRC) in an animal model. Study sample enclosed 110 C57BL/6J male mice. Forty underwent dietary supplement safety assessment (20 standard diet and 20 enriched formulation). Seventy were treated with azoxymethane (AOM)/dextran sulfate sodium and divided into two groups: 35 received standard diet and 35 enriched formulation (curcumin, boswellic acids, silymarin and maltodextrins). Miniature colonoscopy demonstrated colitis and solid lesion development in five mice/group 100 days after first AOM injection. Mice were killed after 10 days. In each group, four subgroups received intraperitoneal bromodeoxyuridine (BrdU) injection at 24th/48th/72nd/96th hour before killing. Anti-inflammatory effect and chemoprevention were evaluated by lesion number/size, histological inflammation/dysplasia/neoplasia assessment, pro-inflammatory cytokine messenger RNA (mRNA), ER-beta/ER-alpha/BrdU immunohistochemistry and TUNEL immunofluorescence. Standard formulation assumption was associated with colon shortening compared with enriched one (P = 0.04), which reduced solid lesion number and size (P < 0.001 for both), histological inflammation score (P = 0.04), pro-inflammatory cytokine mRNA expression (P < 0.001), number of low-grade dysplasia (LGD; P = 0.03) and high-grade dysplasia (P < 0.001) areas. CRC was observed in 69.6% in standard and 23.5% in enriched formulation assuming animals (P < 0.001). Enriched formulation induced lower ER-alpha expression in CRC (P < 0.001) and higher ER-beta expression in LGD (P < 0.001) being associated to higher epithelial turnover (BrdU; P<0.001) in normal mucosa and increased apoptosis in LGD and CRC (P < 0.001 for both). Our results are promising for a successful anti-inflammatory and chemopreventive effect of enriched formulation in CRC arising from inflamed tissue.

SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress.

Sirtuin 1 (SIRT1) is a key player in liver physiology and a therapeutic target against hepatic inflammation. We evaluated the role of SIRT1 in the proinflammatory context and oxidative stress during acetaminophen (APAP)-mediated hepatotoxicity. SIRT1 protein levels decreased in human and mouse livers following APAP overdose. SIRT1-Tg mice maintained higher levels of SIRT1 on APAP injection than wild-type mice and were protected against hepatotoxicity by modulation of antioxidant systems and restrained inflammatory responses, with decreased oxidative stress, proinflammatory cytokine messenger RNA levels, nuclear factor kappa B (NFκB) signaling, and cell death. Mouse hepatocytes stimulated with conditioned medium of APAP-treated macrophages (APAP-CM) showed decreased SIRT1 levels; an effect mimicked by interleukin (IL)1β, an activator of NFκB. This negative modulation was abolished by neutralizing IL1β in APAP-CM or silencing p65-NFκB in hepatocytes. APAP-CM of macrophages from SIRT1-Tg mice failed to downregulate SIRT1 protein levels in hepatocytes. In vivo administration of the NFκB inhibitor BAY 11-7082 preserved SIRT1 levels and protected from APAP-mediated hepatotoxicity. Our work evidenced the unique role of SIRT1 in APAP hepatoprotection by targeting oxidative stress and inflammation. SIRT1 protein levels are downregulated by IL1β/NFκB signaling in APAP hepatotoxicity, resulting in inflammation and oxidative stress. Thus, maintenance of SIRT1 during APAP overdose by inhibiting NFκB might be clinically relevant. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Rafael de Cabo, Joaquim Ros, Kalervo Hiltunen, and Neil Kaplowitz. Antioxid. Redox Signal. 28, 1187-1208.

Optimal ex vivo lung perfusion techniques with oxygenated perfusate

Accumulating evidence supports an increasing role of ex vivo lung perfusion (EVLP) in clinical lung transplantation. However, EVLP has adverse effects on the quality of lung grafts, which have rarely been discussed. Careful optimization of current EVLP protocols might improve outcomes. This study examined effects of different levels of oxygenation of the perfusate circulated through the lungs during EVLP and the impact on post-transplant functional outcomes. We compared results of 4 different oxygenation levels in the perfusate during EVLP: 6% oxygen (O2), 40% O2, 60% O2, and 100% O2. We evaluated lung function, compliance, and vascular resistance and levels of glucose and other markers in the perfusate. After EVLP, lung grafts were transplanted, and post-transplant outcomes were compared. Lungs perfused with 40% O2 on EVLP had the lowest glucose consumption compared with the other perfusates. Lungs treated with 40% O2 or 60% O2 exhibited significantly less inflammation, as indicated by reduced pro-inflammatory cytokine messenger RNA levels compared with lungs perfused with 6% O2 or 100% O2. Significantly more oxidative damage was noted after 4 hours of EVLP perfused with 100% O2. After transplantation, lungs perfused with 40% O2 during EVLP had the best post-transplant functional outcomes. Optimization of O2 levels in the perfusate during EVLP improved outcomes in this rat model. Deoxygenated perfusate, the current standard during EVLP, exhibited significantly more inflammation with compromised cellular metabolic activity and compromised post-transplant outcomes.

Glutamine Modulates Changes in Intestinal Intraepithelial γδT-Lymphocyte Expressions in Mice With Ischemia/Reperfusion Injury.

This study investigated the effect of glutamine (GLN) on expressions of small intestinal intraepithelial lymphocyte (IEL) γδT-cell proinflammatory cytokines and apoptotic regulatory factor genes in a mouse model of hindlimb ischemia/reperfusion (IR) injury. Mice were assigned to a normal control group and three IR groups. Mice in the normal control group received no ischemia treatment, whereas IR groups had hindlimb ischemia for 90 min with subsequent 0 (IR0) or 24 h (IR24) of reperfusion. The IR0 group was sacrificed immediately after reperfusion. The IR24S group was injected with saline, and the IR24G group was given 0.75 g GLN/kg of body weight once via a tail vein before reperfusion. The IR24 groups were sacrificed 24 h after reperfusion. Small intestinal IEL γδT cells of the animals were isolated for further analysis. Results showed that IR injury resulted in lower small intestinal IEL γδT-cell percentages and higher proinflammatory cytokine messenger RNA expressions of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α by IEL γδT cells. Compared with the IR24S group, the IR24G group had a higher IEL γδT-cell percentage. Multiples of change of messenger RNA of proliferation gene expressions of the antiapoptotic Bcl-xl (B-cell lymphoma-extra large) and IL-7 receptor in the IR24G group were higher, whereas expressions of the keratinocyte growth factor and bacterial lectin regenerating islet-derived (Reg)IIIγ were lower in IEL γδT cells. Histological findings also showed that damage to the intestinal mucosa was less severe in the IR group with GLN. These results indicated that a single dose of GLN administered before reperfusion maintained small intestinal IEL γδT cell populations and reduced expressions of intestinal inflammatory cytokines, which may have consequently ameliorated the severity of IR-induced small intestinal epithelial injury.

Amyloid-β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset

Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an endogenous anti-apoptotic bile acid with potent neuroprotective properties in several experimental models of AD. We have previously reported the therapeutic efficacy of TUDCA treatment before amyloid plaque deposition in APP/PS1 double-transgenic mice. In the present study, we evaluated the protective effects of TUDCA when administrated after the onset of amyloid pathology. APP/PS1 transgenic mice with 7 months of age were injected intraperitoneally with TUDCA (500 mg/kg) every 3 days for 3 months. TUDCA treatment significantly attenuated Aβ deposition in the brain, with a concomitant decrease in Aβ1-40 and Aβ1-42 levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Aβ production. In addition, TUDCA abrogated GSK3β hyperactivity, which is highly implicated in tau hyperphosphorylation and glial activation. This effect was likely dependent on the specific activation of the upstream kinase, Akt. Finally, TUDCA treatment decreased glial activation and reduced proinflammatory cytokine messenger RNA expression, while partially rescuing synaptic loss. Overall, our results suggest that TUDCA is a promising therapeutic strategy not only for prevention but also for treatment of AD after disease onset.

Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is seen as the clinical manifestation of a low-grade cerebral edema associated with oxidative-nitrosative stress. However, comprehensive data on HE-associated molecular derangements in the human brain are lacking. In the present study, we used a whole human genome microarray approach for gene expression profiling in post mortem brain samples from patients with cirrhosis with or without HE and controls without cirrhosis. Altered expression levels were found for a total of 1,012 genes in liver cirrhosis patients without and with HE, and HE-characteristic gene expression changes were identified. Genes with altered expression pattern in HE were related to oxidative stress, microglia activation, receptor signaling, inflammatory pathways, cell proliferation, and apoptosis. Despite an up-regulation of genes associated with microglia activation, pro-inflammatory cytokine messenger RNA profiles remained unchanged in the brains of patients with liver cirrhosis and HE compared with controls. Interestingly, many genes counteracting pro-inflammatory signaling and inflammatory cytokine expression were up-regulated in the cerebral cortex of patients with liver cirrhosis and HE. Pathogenetic mechanisms of HE deduced from cell culture and animal experiments, such as oxidative stress, altered Zn(2+) homeostasis and microglia activation also apply to human brain from patients with liver cirrhosis and HE. The study also revealed a not-yet recognized increased expression of genes antagonizing proinflammatory signaling and inflammatory cytokine expression. (HEPATOLOGY 2013;57:2436-2447).

Contribution of interleukin 17A to the development and regulation of allergic inflammation in a murine allergic rhinitis model

BackgroundInterleukin (IL) 17A, a key cytokine of TH17 cells, is a well-known proinflammatory cytokine. Despite the important role of TH17 cells in acute airway inflammation, the role of IL-17A in allergic rhinitis (AR) remains unclear. ObjectiveTo investigate the role of IL-17A in the allergic response in AR. MethodsWild-type BALB/c and IL-17A–deficient mice were immunized intraperitoneally and were challenged intranasally with ovalbumin. Allergic symptom scores, eosinophil infiltration, serum IgE level, and the levels of several cytokines in nasal lavage fluid and splenocyte supernatants were analyzed. ResultsIL-17A levels increased significantly more in ovalbumin-sensitized wild-type mice than in the negative control group. IL-17A–deficient mice showed a significant decrease in allergic symptoms, serum IgE levels, and eosinophil infiltration into the nasal mucosa compared with wild-type mice. IL-17A–deficient mice also showed decreased histamine and cysteinyl leukotriene release. Bone marrow–derived mast cells from IL-17A–deficient mice showed significantly lower degranulation and secretion of tumor necrosis factor α. Moreover, IL-17A deficiency attenuated the IL-5 level in nasal lavage fluid and its production in response to ovalbumin but did not increase interferon γ production and its level in nasal lavage fluid. In addition, secretion of IL-17A from spleen cells induced the expression of proinflammatory cytokine messenger RNA in macrophages. The mean level of proinflammatory cytokines, including tumor necrosis factor α and IL-17, decreased in IL-17A–deficient mice. ConclusionThese results suggest that IL-17A may partly contribute to the development of nasal allergic inflammation in an AR animal model and regulate AR via the activation of proinflammatory cytokines and modulation of TH2 cytokine.

Cortistatin Is Induced in Brain Tissue and Exerts Neuroprotection in a Rat Model of Bacterial Meningoencephalitis

There are fewer reports of brain infection by Klebsiella pneumoniae than there are in other organs, but an increase incidence and morbidity has been noted. We have previously developed a rat model of K. pneumoniae meningoencephalitis. Cortistatin (CST) is a recently discovered neuropeptide with endocrine activities in humans. In this study, we found that brain infection by K. pneumoniae increased endogenous prepro-CST messenger RNA expression, which occurred earlier than did leukocyte infiltration in vivo and also occurred in cultured neuron-glia. Postinfection treatment with CST (either intracerebroventricularly or intraperitoneally), but not somatostatin, reduced leukocyte recruitment and clinical illness as revealed by fever and clinical score in vivo. Postinfection increases of proinflammatory cytokine messenger RNA levels were attenuated by CST in neuron-glia cultures, further confirming a direct effect on neuroinflammation. Administration of CST resulted in less postinfection neuronal loss in vitro, suggesting a direct neuroprotective effect and potential as an adjuvant for treating bacterial meningoencephalitis.

The Effect of Smoking on the Transcriptional Regulation of Lung Inflammation in Patients with Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is believed to result from an abnormal inflammatory response in the lungs to noxious particles and gases usually found in cigarette smoke. In this study, the molecular mechanisms for the enhanced proinflammatory cytokine gene transcription in COPD were investigated. Lung tissue was examined from 56 subjects undergoing resection for peripheral lung tumors as follows: current smokers with (n = 14) and without COPD (n = 17), ex-smokers with COPD (n = 13), and nonsmokers (n = 12). The levels of inhibitor kappaB-alpha (IkappaB-alpha), histone deacetylase 2 (HDAC2), acetylated (ac-) histone H3 and H4, the transcription factor nuclear factor-kappaB (NF-kappaB), proinflammatory cytokine messenger RNA, and 8-isoprostane were measured. IkappaB-alpha levels were significantly decreased in healthy smokers and current and ex-smoking patients with COPD when compared with nonsmokers (p < 0.001), with an associated increase in NF-kappaB DNA binding in current smokers (p < 0.05). An increase in acetylated histone 4 (ac-H4; p < 0.01) was found in current smokers. Conversely, ex-smokers with COPD showed an increase in ac-H3 (p < 0.05). Decreased levels of cytoplasmic, but not nuclear, HDAC2 protein levels were detected. From the cytokine profiles, no significant differences were detected; however, interleukin-12p40 expression correlated with ac-H4 in current smokers with COPD (p < 0.01). These data propose a role for modification of nucleosomal structure in inflammatory cytokine gene transcription in response to smoking. The imbalance between histone deacetylation and acetylation in favor of acetylation may contribute to the enhanced inflammation in smokers susceptible to the development of COPD.

Preventive and therapeutic effects of NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid

To ascertain the molecule mechanism of nuclear factor-kappaB (NF-kappaB) inhibitor curcumin preventive and therapeutic effects in rats' colitis induced by trinitrobenzene sulfonic acid (TNBS). Sixty rats with TNBS-induced colitis were treated with 2.0% curcumin in the diet. Thirty positive control rats were treated with 0.5% sulfasalazine (SASP). Thirty negative control rats and thirty model rats were treated with general diet. Changes of body weight together with histological scores were evaluated. Survival rates were also evaluated. Cell nuclear NF-kappaB activity in colonic mucosa was evaluated by using electrophoretic mobility shift assay. Cytoplasmic IkappaB protein in colonic mucosa was detected by using Western Blot analysis. Cytokine messenger expression in colonic tissue was assessed by using semiquantitative reverse-transcription polymerase chain reaction. Treatment with curcumin could prevent and treat both wasting and histopathologic signs of rats with TNBS-induced intestinal inflammation. In accordance with these findings, NF-kappaB activation in colonic mucosa was suppressed in the curcumin-treated groups. Degradations of cytoplasmic IkappaB protein in colonic mucosa were blocked by curcumin treatment. Proinflammatory cytokine messenger RNA expression in colonic mucosa was also suppressed. This study shows that NF-kappaB inhibitor curcumin could prevent and improve experimental colitis in murine model with inflammatory bowel disease (IBD). The findings suggest that NF-kappaB inhibitor curcumin could be a potential target for the patients with IBD.

Neutrophil and Small Intestinal Lymphocyte Migration After Salmonella typhimurium Infection: Impact of Fermentable Fiber

ABSTRACTObjectives:Formula‐fed infants have more episodes of acute diarrhea and intestinal infection than do breast‐fed infants. Nutrient additions to infant formula that could confer some of the immune benefits of breast milk to formula‐fed infants are currently under investigation. This study examined the impact of enteral formulas supplemented with fermentable substrates on small intestinal lymphocyte and neutrophil migration in piglets infected with Salmonella typhimurium. Small intestinal proin‐flammatory cytokine messenger RNA abundance and in vitro lipopolysaccharide‐stimulated interleukin‐6 release in whole blood were assessed.Methods:Piglets were randomized to receive sow milk replacer formula supplemented with methylcellulose (control), soy polysaccharides (SPS) or fructooligosaccharides (FOS). On day 7, half of the piglets were infected with S. typhimurium. Intestinal lymphocyte, neutrophil and whole blood samples were obtained on day 14.Results:After infection, there was decreased lymphocyte migration in the control group but not in the SPS and FOS groups. The SPS group had greater neutrophil migration compared with the control and FOS groups, regardless of infection. Small intestinal abundance of proinflammatory cytokine messenger RNA was not significantly changed by either infection or diet. Blood from the FOS group challenged with lipopolysaccharide for 2 hours exhibited decreased interleukin‐6 production compared with blood from the control and SPS groups, regardless of infection.Conclusions:Supplementation of enteral formulas with SPS maintains the migratory function of small intestinal lymphocytes while increasing that of neutrophils.

Alteration of somatotropic function by proinflammatory cytokines.

Infections direct amino acids away from growth and skeletal muscle accretion toward the hepatic synthesis of acute-phase proteins. The loss of skeletal muscle protein stores results in both a decrease in muscle function and an increase in mortality. In general, muscle protein synthesis is decreased in rodent models of sepsis, as well as after the injection of components of the bacterial cell wall, such as lipopolysaccharide. Although the overexpression of proinflammatory cytokines is known to hasten the loss of skeletal muscle protein, it is not known whether this represents a direct effect of cytokines or results from secondary changes in the IGF system. Plasma concentrations of IGF-I are dramatically lowered by infection in rats, mice, pigs, and steers. The drop in IGF-I often occurs despite an increase in the plasma concentration of somatotropin. Animals are therefore considered to be GH resistant. The IGF bioactivity is determined not only by the plasma concentration of the ligand, but also by IGFBP; IGFBP-3 is the most abundant of these binding proteins and undergoes proteolysis during some catabolic states. In contrast to IGFBP-3, the plasma concentration of inhibitory IGFBP, such as IGFBP-1, is increased during infection. Insulin-like growth factor-binding protein-1 accumulates in skeletal muscle, where it can potentially inhibit IGF-dependent protein synthesis. Insulin-like growth factor-I and IGFBP-1 are regulated at the level of gene transcription by proinflammatory cytokines. Recent studies demonstrate that bacterial components that activate immune cells also activate the innate immune response in skeletal muscle. Lipopolysaccharide increases proinflammatory cytokine messenger RNA expression in muscle from control mice, but not from mice with a mutation in the lipopolysaccharide receptor. Lipopolysaccharide also increases cytokine expression in human and mouse myoblasts. Local expression of cytokines in skeletal muscle may negatively regulate the autocrine synthesis of IGF-I. Current work is focused on deciphering the mechanism by which muscle becomes GH resistant and the development of therapies to maintain muscle protein stores during infection.

Curcumin prevents and ameliorates trinitrobenzene sulfonic acid–induced colitis in mice

Background & Aims: Curcumin is known to have a variety of pharmacologic effects, including antitumor, anti-inflammatory, and anti-infectious activities. The pleiotropic effects of curcumin are attributable at least in part to inhibition of transcriptional factor nuclear factor κB (NF-κB). However, the effect of curcumin on intestinal inflammation has hitherto not been evaluated. The aim of this study was to determine whether treatment with curcumin prevents and ameliorates colonic inflammation in a mouse model of inflammatory bowel disease. Methods: Mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis were treated with 0.5%, 2.0%, or 5.0% curcumin in the diet, and changes in body weight together with histologic scores were evaluated. Colonic T-cell subsets were characterized, and NF-κB in colonic mucosa was detected by immunohistochemistry. NF-κB activity in the colonic mucosa was evaluated using electrophoretic mobility shift assay. Cytokine messenger RNA expression in colonic tissue was assessed by semiquantitative reverse-transcription polymerase chain reaction. Results: Treatment of mice with curcumin prevented and improved both wasting and histopathologic signs of TNBS-induced colonic inflammation. Consistent with these findings, CD4+ T-cell infiltration and NF-κB activation in colonic mucosa were suppressed in the curcumin-treated group. Suppression of proinflammatory cytokine messenger RNA expression in colonic mucosa was also observed. Conclusions: This study has shown for the first time that treatment with curcumin can prevent and improve murine experimental colitis. This finding suggests that curcumin could be a potential therapeutic agent for the treatment of patients with inflammatory bowel disease.GASTROENTEROLOGY 2002;123:1912-1922

Cytokine gene profile in gastric mucosa in Helicobacter pylori infection and Zollinger-Ellison syndrome

OBJECTIVE: Helicobacter pylori-associated inflammation is mediated, in part, by inflammatory cytokines. In contrast, the mucosal disease associated with Zollinger-Ellison syndrome (ZES) is acid driven, and the role of cytokines is not known. The aim of this study was to elucidate the role of cytokines in these two diseases, as we quantitated proinflammatory cytokine messenger RNA (mRNA) levels in the gastric mucosa from patients with H. pylori infection and ZES. METHODS: The study population included 11 patients with H. pylori infection, 12 with ZES, 17 with both H. pylori infection and ZES, and three control subjects with neither. Using a competitive polymerase chain reaction for interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α, the polymerase chain reaction products in gastric biopsies were quantitated by capillary electrophoresis and laser-induced fluorescence. RESULTS: The levels of IL-1β, IL-6, IL-8, and tumor necrosis factor-α mRNA in gastric tissue of patients with H. pylori infection only and ZES only exceeded the levels in the control gastric tissue ( p < 0.05 to p < 0.005). Unexpectedly, the number of molecules of IL-1β and IL-8 mRNA in gastric tissue from ZES patients exceeded the levels in gastric tissue from patients with H. pylori only ( p < 0.05). The local levels of cytokine mRNA in patients with both diseases exceeded the levels in patients with H. pylori only (IL-6, p < 0.05; IL-8, p < 0.05) and ZES only (IL-6, p < 0.05; tumor necrosis factor-α, p < 0.05). CONCLUSIONS: Levels of proinflammatory cytokine mRNA are increased in acid-driven as well as infection-driven gastric inflammation, and the presence of both disease processes appears to have an additive effect on local cytokine message expression. Inflammatory cytokines may mediate both infection- and acid-driven gastric inflammation.