Release Of Anti-inflammatory Mediators Research Articles

Nerve Growth Factor Downregulates Inflammatory Response in Human Monocytes through TrkA

Nerve growth factor (NGF) levels are highly increased in inflamed tissues, but their role is unclear. We show that NGF is part of a regulatory loop in monocytes: inflammatory stimuli, while activating a proinflammatory response through TLRs, upregulate the expression of the NGF receptor TrkA. In turn, NGF, by binding to TrkA, interferes with TLR responses. In TLR-activated monocytes, NGF reduces inflammatory cytokine production (IL-1β, TNF-α, IL-6, and IL-8) while inducing the release of anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist). NGF binding to TrkA affects TLR signaling, favoring pathways that mediate inhibition of inflammatory responses: it increases Akt phosphorylation, inhibits glycogen synthase kinase 3 activity, reduces IκB phosphorylation and p65 NF-κB translocation, and increases nuclear p50 NF-κB binding activity. Use of TrkA inhibitors in TLR-activated monocytes abolishes the effects of NGF on the activation of anti-inflammatory signaling pathways, thus increasing NF-κB pathway activation and inflammatory cytokine production while reducing IL-10 production. PBMC and mononuclear cells obtained from the synovial fluid of patients with juvenile idiopathic arthritis show marked downregulation of TrkA expression. In ex vivo experiments, the addition of NGF to LPS-activated juvenile idiopathic arthritis to both mononuclear cells from synovial fluid and PBMC fails to reduce the production of IL-6 that, in contrast, is observed in healthy donors. This suggests that defective TrkA expression may facilitate proinflammatory mechanisms, contributing to chronic tissue inflammation and damage. In conclusion, this study identifies a novel regulatory mechanism of inflammatory responses through NGF and its receptor TrkA, for which abnormality may have pathogenic implications for chronic inflammatory diseases.

N2 Neutrophils, Novel Players in Brain Inflammation After Stroke

Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor-γ dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor-γ activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome. Brain sections and cell suspensions were prepared from mice exposed to permanent distal middle cerebral artery occlusion. Double immunostaining with stereological counting of brain sections and flow-cytometry analysis of brain cell suspensions were performed. Rosiglitazone accelerated neutrophil infiltration to the ischemic core, concomitantly to neuroprotection. Some neutrophils (≈31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, most neutrophils (≈77%) acquired an N2 phenotype. Interestingly, rosiglitazone increased neutrophil engulfment by microglia/macrophages, a clearance that preferentially affected the N2 subset. We present the first evidence of neutrophil reprogramming toward an N2 phenotype in brain inflammation, which can be modulated by activation of the peroxisome proliferator-activated receptor-γ nuclear receptor. We also show that N2 polarization is associated with an increased neutrophil clearance, thus suggesting that this switch is a crucial event for resolution of inflammation that may participate in neuroprotection.

Human intrahepatic biliary epithelial cells engulf blebs from their apoptotic peers

The phagocytic clearance of apoptotic cells is critical for tissue homeostasis; a number of non-professional phagocytic cells, including epithelial cells, can both take up and process apoptotic bodies, including the release of anti-inflammatory mediators. These observations are particularly important in the case of human intrahepatic biliary cells (HiBEC), because such cells are themselves a target of destruction in primary biliary cirrhosis, the human autoimmune disease. To address the apoptotic ability of HiBECs, we have focused on their ability to phagocytize apoptotic blebs from autologous HiBECs. In this study we report that HiBEC cells demonstrate phagocytic function from autologous HiBEC peers accompanied by up-regulation of the chemokines CCL2 [monocyte chemotactic protein-1 (MCP-1)] and CXCL8 [interleukin (IL)-8]. In particular, HiBEC cells express the phagocytosis-related receptor phosphatidylserine receptors (PSR), implying that HiBECs function through the 'eat-me' signal phosphatidylserine expressed by apoptotic cells. Indeed, although HiBEC cells acquire antigen-presenting cell (APC) function, they do not change the expression of classic APC function surface markers after engulfment of blebs, both with and without the presence of Toll-like receptor (TLR) stimulation. These results are important not only for understanding of the normal physiological function of HiBECs, but also explain the inflammatory potential and reduced clearance of HiBEC cells following the inflammatory cascade in primary biliary cirrhosis.

Monocyte Deactivation Correlates With Injury Severity Score, But Not With Heme Oxygenase-1 Levels in Trauma Patients

Traumatic injury induces a local and systemic release of pro-inflammatory cytokines, acute phase proteins, hormones, and other inflammatory mediators. The excessive release of these mediators plays an important role in the pathogenesis of shock. In parallel to this pro-inflammatory response, there is a regulatory response characterized by the release of anti-inflammatory mediators, which is thought to represent the host's attempt to restore immunological equilibrium. Studies in septic patients have suggested the compensatory anti-inflammatory response may result in an "immunodeficient state" that leaves the host susceptible to further infectious insults. A key feature of the anti-inflammatory state in septic patients is a change in the responsiveness of monocytes that has been termed "monocyte deactivation." This is supported by data that link monocyte deactivation to increased mortality in septic patients. Monocytes with reduced HLA-DR expression have been described in trauma patients. We collected blood from 25 severely injured patients and evaluated peripheral blood mononuclear cells (PBMC) for HLA-DR expression and TNF-α response to LPS stimulation as markers of monocyte deactivation. Levels of intracellular HO-1 were determined in each patient, as HO-1 has been implicated in monocyte deactivation in patients with severe systemic inflammatory response syndrome (SIRS). HLA-DR expression correlated inversely with Injury Severity Scores and TNF-α response to LPS stimulation, but failed to correlate with HO-1 levels in these patients. HLA-DR expression was decreased in normal monocytes stimulated with patient plasma, but this treatment had no effect on HO-1 levels. These results suggest monocyte deactivation in trauma patients is unlikely to be mediated by HO-1.

Induction of Apoptosis by Crambene Protects Mice against Acute Pancreatitis via Anti-Inflammatory Pathways

Apoptosis is a teleologically beneficial form of cell death in acute pancreatitis. Our previous work has demonstrated that induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis. However, little is known about how the induction of apoptosis reduces the severity of acute pancreatitis. Because the clearance of apoptotic cells might suppress inflammation and critically regulate immune responses, we postulate that clearance of apoptotic cells stimulates an anti-inflammatory response, which has a protective action against acute pancreatitis. To test this hypothesis, induction of apoptosis in acute pancreatitis in vivo and co-cultures of peritoneal resident macrophages with apoptotic acinar cells in vitro were used as experimental systems, testing expression of phagocytic receptors and levels of inflammatory mediators. Moreover, neutralizing anti-interleukin (IL)-10 monoclonal antibody (2.5 mg/kg) was used before the induction of apoptosis in acute pancreatitis, testing whether the protection from apoptosis induction would be removed. Our study showed that clearance of apoptotic acinar cells, which may occur essentially through the CD36-positive macrophage, stimulates the release of anti-inflammatory mediators like IL-10. IL-10 plays an important role in crambene-induced protection in acute pancreatitis. Thus, induction of pancreatic acinar cell apoptosis by crambene protects mice against acute pancreatitis via induction of anti-inflammatory pathways.

IKKα in the regulation of inflammation and adaptive immunity

Inflammation is a beneficial response to insult or injury which plays an important role in orchestrating the adaptive immune response. The resolution of acute inflammation is an active process that involves the release of anti-inflammatory mediators and the termination of pro-inflammatory signalling pathways coincident with leucocyte apoptosis and phagocytic clearance and the migration of antigen-presenting cells from the site of inflammation to the local lymphatic tissue. The latter process is required for the development of adaptive immunity and immunological memory. The NF-kappaB (nuclear factor kappaB) pathway is an important regulator of inflammation and immunity; NF-kappaB activation is controlled by IKK [IkappaB (inhibitor of NF-kappaB) kinase] complex, which regulates NF-kappaB activation in response to pro-inflammatory stimuli. The IKK complex has two catalytic subunits, IKKalpha and IKKbeta; recent research shows that these highly homologous kinases have distinct roles in inflammation and adaptive immunity. Here, we discuss the emerging roles for IKKalpha in the tight regulation of inflammation and the development of adaptive immune responses.

Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression

Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-beta, prostaglandin E(2), and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer.

Portal hypertension produces an evolutive hepato-intestinal pro- and anti-inflammatory response in the rat

An inflammatory etiopathogeny can be suggested in portal hypertensive enteropathy since infiltration of the intestinal wall by mononuclear cells has been described in this condition. This work was carried out with the intention of shedding light on this matter. Male Wistar rats were divided into 4 control groups and 4 groups with partial portal vein ligation at 1, 2, 3 and 15 months. TNF-α, IL-1β and IL-10 were quantified in liver and ileum by ELISA. CO and NO were measured in splanchnic and systemic vein by spectrophotometry and Griess reaction, respectively. Expression of constitutive and inducible isoforms of NO and HO were assayed by Western blot in liver and ileum. An increased hepatic release of proinflammatory mediators (TNF-α, IL-1β and NO) associated with intestinal release of anti-inflammatory mediators (IL-10, CO) occurs in an early evolutive phase (1 month) of experimental portal hypertension. On the contrary, in the long-term (15 months), the increase in the intestinal release of proinflammatory mediators (TNF-α, IL-1β) is associated with an increase in the hepatic release of anti-inflammatory mediators (IL-10, CO). These results suggest that experimental prehepatic portal hypertension presents changes in the serum and tissular (liver and small bowel) concentrations of mediators which are considered as pro- and anti-inflammatory.

Thymulin: An Emerging Anti-Inflammatory Molecule

Thymulin is a neuroendocrine hormone with immunoregulatory actions. Originally known as 'serum thymic factor' (FTS), thymulin binds to a carrier protein and zinc (Zn2+) to exert its biologic properties. Thymulin, albeit an es- sential hormone for the T lymphocyte differentiation and the normalization of the ratio of T-helper cells to suppressor cells, accumulating evidence suggests its involvement in inflammations of various etiologies. Recently, thymulin has been shown to have anti-nociceptive effects in hyperalgesia and in pain of neurogenic origin, ostensibly through action on sen- sory afferents and the release of anti-inflammatory mediators. Given its anti-inflammatory potential, thymulin downregu- lates the release of inflammatory mediators, such as cytokines and chemokines, upregulates anti-inflammatory factors, such as interleukin (IL)-10, and exerts molecular control via the regulation of transcription factors and mediators. Recent evidence tends to indicate that thymulin can be a therapeutic agent in many inflammatory diseases and in pathological conditions affecting the peripheral and/or the central nervous system. This review discusses current concepts in the anti- inflammatory actions of thymulin and correlates this activity with an emerging theme for therapeutic treatment.

The contribution of radiation-induced injury to the gastrointestinal tract in the development of multi-organ dysfunction syndrome or failure

Severe damage to the gastrointestinal tract (GIT), such as loss of the gastrointestinal mucosa and haemorrhage, following accidental overexposure to ionising radiation appears to be a determinant feature in patient mortality. Injury to the GIT may be direct, as this tissue is particularly radiation sensitive, as well as indirect as a result of radiation burns and bone marrow aplasia. Similar to other severe trauma situations such as thermal burns, radiation exposure results in reduced intestinal barrier integrity, which initiates and/or perpetuates inflammatory–anti-inflammatory mediator release. This may result in damage to distant organs. In this context, the injured gut may be considered as a “key player” or “motor” in the development of multiple organ dysfunction syndrome or failure. Of note is that radiation exposure elicits similar GIT injury of both mucosal and vascular elements, in contrast to other severe physical insults. Common factors are the intestinal inflammatory response and loss of barrie...

The role of the macrophage in apoptosis: hunter, gatherer, and regulator.

Clearance of cellular corpses is a critical feature of apoptosis in vivo during development, tissue homeostasis, and resolution of inflammation. As the professional phagocytes of the body, macrophages play a key role in this process. By recognizing emerging signals using several different receptors, macrophages engulf apoptotic cells swiftly and efficiently. In addition, the binding of apoptotic cells profoundly down-regulates the ability of the macrophage to produce inflammatory mediators by inducing the release of antiinflammatory mediators. Finally, macrophages may actually induce cell death in specific cells during embryogenesis. Abnormalities of apoptotic cell clearance may contribute to the pathogenesis of chronic inflammatory diseases, including those of autoimmune etiology. It is also possible that certain malignant tumor cells co-opt the mechanisms for apoptotic cell clearance to avoid immune surveillance by subverting macrophage and dendritic cell responses.

Intra-hepatic expression of scavenger receptor and CD14 and their relationship with local inflammatory responses in endotoxemia in mice.

Our objective was to investigate the expression of scavenger receptor (SR) and CD14 in the liver and their relationship with local anti-inflammatory and proinflammatory responses in endotoxemia in order to uncover the mechanism for the liver to turn into effector organ from defense one at the level of cell receptors in sepsis. Mouse models of endotoxemia of different severity were reproduced by injection of different doses of lipopolysaccharide (LPS) via tail vein. Expression of SR and CD14 in the liver was assayed by immunohistochemistry and was then analyzed with an image analysis system. The levels of TNFalpha, IL-6, IL-4, and IL-10 in liver tissue were determined with ELISA. Expression of SR in the liver in the high-dose group was markedly decreased 1 h after injection of LPS, and also in low- and medium-dose groups at 3 h. The expression of SR in the liver in the three groups was shown to be progressively decreased with the time prolonged. There was significant difference in average optical density (OD) values of SR among the three groups. The expression of CD14 in the liver in the three groups was shown to be significantly increased 1 h after injection of LPS, and much more with the time prolonged. But there was no significant difference in OD values of CD14 among the three groups. The contents of intrahepatic proinflammatory mediators TNFalpha and IL-6 and anti-inflammatory mediators IL-4 and IL-10 were successively significantly increased after injection of LPS. The release of anti-inflammatory mediators was shown to be later than that of proinflammatory mediators. Correlation analysis indicated that there was negative correlation between expression of SR and CD14, and that changes of TNFalpha, IL-6, IL-4, and IL-10 levels in liver tissues were correlated significantly positively with OD values of CD14 and negatively with OD values of SR. Expression of SR in the liver was shown to be progressively decreased, and that of CD14 increased in endotoxemia, which was closely related to the uncontrolled inflammatory response in liver. This might be an important mechanism for the liver to turn into effector organ from defense one in sepsis.

Role of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in brain-mediated compensatory antiinflammatory response

Local infection or trauma induce a local inflammatory response. The release of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 activates an inflammatory cascade improving wound healing and antimicrobial defence. Overwhelming response, however, can result in systemic inflammatory response syndrome (SIRS) and septic shock. In order to control the potentially harmful inflammatory response, the immune system can release several antiinflammatory mediators like IL-10, IL-1 receptor antagonist (ra), and soluble TNF-α receptors. TNF-α, IL-1β and prostaglandins by themselves are powerful inducers of the compensatory antiinflammatory response syndrome (CARS). However, there are evidences that in addition to the autoregulatory pathways of the immune cells the delicate balance between pro- and antiinflammatory response is controlled by central mechanisms. Hence, a bidirectional communication between the immune and central nervous system (CNS) exists and is most evident in the increase in secretion of different neuromodulators and neurohormones that follows systemic inflammation. Moreover, in vitro studies demonstrate that these neuromediators, especially glucocorticoids and catecholamines, predominantly decrease the secretion of proinflammatory cytokines (IL-1, IL-6 and TNF-α) and increase the release of antiinflammatory mediators like IL-10 and transforming growth factor-β. Consequently, the activation of the neuroimmune pathways reduces the intensity of the immune response and prevents an overwhelming inflammatory immune reaction. If the immunoinhibitory CNS pathways are activated without systemic inflammation, however, a brain-mediated immunodepression can develop. This activation can result from the production of cytokines in the brain following infection, injury, and ischemia or in response to different stressors (life events, depression, anxiety etc) or directly from brain stem irritation. In summary, mediators of the CNS are implicated in the regulation of immune functions and play a role in both conditioning the host's response to endogenous or exogenous stimuli and generating a brain-mediated immunodepression. Biomedical Reviews 2000; 11: 29-38.

Release of anti-inflammatory mediators after major torso trauma correlates with the development of postinjury multiple organ failure

Background: Soluble tumor necrosis factor receptor (sTNFr) and interleukin-1 receptor antagonist (IL-1ra) have been identified as endogenous inhibitors of TNF-α and IL-1β. While TNF-α and IL-1β levels are not systematically elevated in postinjury patients who developed multiorgan failure (MOF), their involvement at the tissue level has been suggested. Our study hypothesis was that levels of sTNFr-I and IL-1ra would discriminate patients at risk for postinjury MOF.Methods: Serial plasma levels of sTNFr and IL-1ra were measured in 29 trauma patients at high risk for postinjury MOF.Results: sTNFr-I levels were higher in MOF compared with non-MOF patients at 12, 84, and 132 hours postinjury. MOF patients also had higher IL-1ra values 36, 60, 84, and 132 hours postinjury.Conclusions: Anti-inflammatory mechanisms are activated after trauma. Since increased levels of sTNFr and IL-1ra correlate with postinjury MOF, they may contribute to our understanding of the pathogenesis as well as prediction of outcome. High levels of antagonists to TNF-α and IL-1β suggest tissue level involvement of these cytokines in postinjury hyperinflammation.

Splenic Immune Suppression in Sepsis: A Role for IL-10-Induced Changes in P38 MAPK Signaling

Background.Studies have indicated that following the induction of sepsis, there is a late (24 h) generalized suppression of the immune response which is associated with increased anti-inflammatory mediator release (e.g., IL-10). However, the mechanisms by which this occurs are unknown. In this regard, recent studies indicate that p38 mitogen-activated protein kinase (p38 MAPK) may play a central role in transducing the signals from immunosuppressive agents which in turn may alter lymphoid cytokine release. The aim of this study, therefore, was to determine whether the anti-inflammatory mediator IL-10 alters splenocyte IL-2 and IFN-γ release, as well as the expression and activation of p38 MAPK in septic animals.Materials and methods.Splenocytes (SPL) (or for some experiments purified T cells) were harvested from mice subjected 24 h earlier to either sepsis by cecal ligation and puncture (CLP) or Sham-CLP and stimulated with 2.5 μg concanavalin A (ConA)/ml in the presence or absence of either monoclonal antibody (Mab) to IL-10 (4 μg/ml) or IgG control. In subsequent studies, sepsis was induced in C57BL/6J and C57BL/6 IL-10 knockout mice, and SPL harvested and stimulated with ConA. SPL cytokine release was measured by ELISA, and the expression and phosphorylation of p38 MAPK were measured by Western analysis.Results.The results indicate that Th1 cytokine (IL-2, IFN-γ) release was depressed by sepsis, while p38 MAPK expression and activity were increased in SPL as well as in T-cells. Neutralization of IL-10 byin vitrouse of anti-IL-10 Mab and in the IL-10 knockout animal restored the Th1 response and caused a downregulation of p38 MAPK expression and activity after CLP. Thus, IL-10 appears to contribute to the increase in p38 MAPK activity and expression and the corresponding suppression of Th1 response seen in late sepsis.

SELECTIVE POTENTIATION OF CYTOKINE EXPRESSION IN HUMAN WHOLE BLOOD BY MURABUTIDE, A MURAMYL DIPEPTIDE ANALOGUE

Murabutide is a synthetic muramyl peptide which is in clinical stage of development. Its effect on cytokine production was analysed in human whole blood to reproduce the natural environment. Induced gene transcription within 2 h was associated with the release of cytokines such as tumour necrosis factor (TNF), interleukin-1 beta (IL–1β), IL–6, IL–8, and also the anti-inflammatory mediator IL–1ra. This synthesis was not associated with the release of IL–4, IL–12, interferon gamma (IFN–γ), the three colony-stimulating factors (CSFs) or the soluble TNF receptors. The same series of cytokines were assayed to determine the effect of some recombinant cytokines in association with murabutide. Thus, in the presence of IL–2, IL–6, IL–3 or granulocyte-macrophage colony-stimulating factor (GM–CSF), the level of cytokines induced by murabutide was enhanced with no change in the other cytokines profile. IL–3 and GM–CSF were more potent in increasing the murabutide-induced response, eliciting synergistic effects on IL–8 and IL–1Ra production, at both the mRNA accumulation and the protein release. Although neither IL–12 nor IFN–γ were produced in cells stimulated with murabutide alone, some mRNA expression was found with combined treatments. The results indicate that association of murabutide with a cytokine could exert synergistic effects, thus reducing effective doses of the recombinant protein, increasing the release of anti-inflammatory mediators, and triggering efficient cellular immunity.

Release of anti-inflammatory mediators after mechanical trauma correlates with severity of injury and clinical outcome.

Excessive synthesis of proinflammatory cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta] after trauma has been correlated with poor outcome. Recently, naturally occurring inhibitors of TNF-alpha and IL-1 beta have been characterized such as soluble TNF receptors (sTNFRs) and IL-1 receptor antagonist (IL-1ra). The present study was undertaken to determine whether injury results in a rise of circulating sTNFRs and IL-1ra. If so, whether plasma levels of these anti-inflammatory mediators correlate with severity of injury and clinical outcome of these patients. Injured patients (n = 213) showed significantly increased sTNFR and IL-1ra plasma levels throughout the observation period of 14 days, compared with healthy volunteers (n = 127). Patients with severe injury (Injury Severity Score > 16 points) revealed higher levels (p < 0.05) of sTNFRs and IL-1ra than patients with minor trauma (Injury Severity Score < or = 16 points). Patients who died from injury demonstrated increased (p < 0.05) sTNFR p55 and IL-1ra plasma levels, compared with survivors. Thus, anti-inflammatory mechanisms are activated after trauma dependent on severity of injury. Because increased plasma levels of anti-inflammatory reacting proteins portended poorly for patient survival, these mediators may contribute to prediction of outcome after severe injury.

Immunopathology of NSAID‐Gastropathy: Inhibitory Effectsn of Interleukin‐I and Cyclosporin Aa

The present study demonstrates that CSA is capable of inhibiting indomethacin-induced leukocyte adherence to the vascular endothelium, and can reduce the severity of indomethacin-induced gastric mucosal injury. These results are therefore consistent with the hypothesis that leukocyte (particularly neutrophil) adherence is a critical event in the pathogenesis of NSAID-induced gastropathy. The mechanism through which CSA inhibits leukocyte adherence is not clear, and warrants further investigation. This study also confirmed the protective effects of IL-1 in experimental NSAID-gastropathy, and demonstrates that one of the ways the IL-1 may protect the mucosa is through its ability to inhibit the release of proinflammatory mediators (e.g., PAF) and promote the release of antiinflammatory mediators (e.g., nitric oxide). IL-1 modulated the release of these mediators from peritoneal mast cells at doses in the pg/ml to ng/ml range. IL-1 can inhibit the ability of neutrophils to respond to chemotactic stimuli and can prevent LTB4-induced neutropenia. Inhibition of neutrophil function by IL-1 may therefore account for its ability to reduce NSAID-induced gastric mucosal injury. Whether or not effects of IL-1 on the production of mediators such as nitric oxide and PAF is an underlying mechanism for the inhibitory effects on neutrophil function remains to be determined.