Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.

BACKGROUND: Studies relating certain chemokine and chemokine receptor gene alleles with the outcome of HIV-1 infection have yielded inconsistent results. OBJECTIVE: To examine postulated associations of genetic alleles with HIV-1 disease progression. DESIGN: Meta-analysis of individual-patient data. SETTING: 19 prospective cohort studies and case-control studies from the United States, Europe, and Australia. PATIENTS: Patients with HIV-1 infection who were of European or African descent. MEASUREMENTS: Time to AIDS, death, and death after AIDS and HIV-1 RNA level at study entry or soon after seroconversion. Data were combined with fixed-effects and random-effects models. RESULTS: Both the CCR5-Delta32 and CCR2-64I alleles were associated with a decreased risk for progression to AIDS (relative hazard among seroconverters, 0.74 and 0.76, respectively; P = 0.01 for both), a decreased risk for death (relative hazard among seroconverters, 0.64 and 0.74; P < 0.05 for both), and lower HIV-1 RNA levels after seroconversion (difference, -0.18 log(10) copies/mL and -0.14 log(10) copies/mL; P < 0.05 for both). Having the CCR5-Delta32 or CCR2-64I allele had no clear protective effect on the risk for death after development of AIDS. The results were consistent between seroconverters and seroprevalent patients. In contrast, SDF-1 3'A homozygotes showed no decreased risk for AIDS (relative hazard for seroconverters and seroprevalent patients, 0.99 and 1.03, respectively), death (relative hazard, 0.97 and 1.00), or death after development of AIDS (relative hazard, 0.81 and 0.97; P > 0.5 for all). CONCLUSIONS: The CCR5-Delta32 and CCR2-64I alleles had a strong protective effect on progression of HIV-1 infection, but SDF-1 3'A homozygosity carried no such protection.

Independent risk of mechanical ventilation for AIDS-related Pneumocystis carinii pneumonia associated with bronchoalveolar lavage neutrophilia.

The use of mechanical ventilation (MV) for AIDS-related Pneumocystis carinii pneumonia (PCP) has varied over time. The introduction of adjunctive corticosteroid therapy has changed the pathophysiology of PCP. In the present study, we attempted to identify factors predictive of severe respiratory failure requiring MV amongst patients with PCP treated in the era of adjunctive corticosteroid therapy. Furthermore, we studied factors associated with survival in relation to MV. Of 170 consecutive patients with AIDS-related PCP, 18 (11%) required MV. Thirteen of 18 ventilated patients died (72%). In a logistic regression analysis, higher age, increased bronchoalveolar lavage (BAL) neutrophilia and a positive BAL cytomegalovirus CMV culture were associated with the need of MV. In multivariate analyses, only BAL neutrophilia remained independently predictive of mechanical ventilation. In conclusion, short-term mortality remained high after the introduction of adjunctive corticosteroid therapy. BAL neutrophilia may be a useful prognostic marker to identify patients at high risk of requiring mechanical ventilation.

Penicillin as empirical therapy for patients hospitalised with community acquired pneumonia at a Danish hospital.

INTRODUCTION: We report on the outcome of a study of patients hospitalised with community acquired pneumonia (HCAP) at a Danish university hospital. METHODOLOGY: In a retrospective study of 243 consecutive patients with radiographically verified HCAP, data on clinical and laboratory findings and outcome parameters were collected. Three groups were established according to the initial choice of antibiotic(s): penicillin only (n = 160); non-allergic patients starting broader spectrum therapy (n = 54); and patients with suspected penicillin allergy (n = 29). RESULTS: The overall mortality within three months was 12% and the readmission rate within three months was 20%. The three treatment groups were comparable with respect to most demographic and clinical criteria at baseline. No significant differences in outcome between the groups were found: the mortality was 12.5%, 13.0%, and 10.3%, respectively, p = 0.94, and the readmission rate 20.3%, 24.0%, and 14.8%, respectively; p = 0.63. CONCLUSION: Patients treated for community-acquired pneumonia at a Danish university hospital had clinical outcomes fully at height with findings from other countries, and half of the patients were successfully treated with penicillin monotherapy. No differences in clinical outcomes were documented between patients treated empirically with broad-spectrum therapy and penicillin monotherapy. Therefore, penicillin seems to be a reasonable first choice for initial therapy of HCAP in Denmark as in other regions with similar patterns of microbial pathogens and resistance.

Clinical correlation of variations in the internal transcribed spacer regions of rRNA genes in Pneumocystis carinii f.sp. hominis.

OBJECTIVES: To analyse the importance of sequence variations in the internal transcribed spacer (ITS) regions 1 and 2 of the nuclear rRNA operon in AIDS patients with Pneumocystis carinii pneumonia (PCP). DESIGN AND METHODS: ITS 1 and 2 genotypes were determined in 162 bronchoalveolar lavage samples from 130 patients participating in a prospective cohort study of PCP. RESULTS: A total of 49 different ITS genotypes were detected. ITS genotype was not associated with the clinical severity or outcome of PCP. In 37 of 162 (23%) samples infection with two or more genotypes was observed. A genotype switch was detected in six of 10 patients (60%) with recurrent episodes of PCP. However, genotype changes were also seen in 10 of 19 patients (53%) who had repeated bronchoscopies within the same episode of PCP. The same ITS type was observed twice in 13 (46%) of the 28 patients with repeat bronchoscopies during single or recurrent episodes of pneumonia, but in only 14 of 81 (17%) randomly selected pairs (P < 0.01). CONCLUSION: Although the detection of ITS genotypes is not a random event, changes in genotype can be detected in a single episode of disease, with 23% of PCP patients being infected with more than one P. carinii genotype, thus complicating the use of this locus as a genetic marker to separate new infection from the reactivation of latent infection. ITS genotypes are not associated with the clinical severity of PCP.

Prognostic markers of short-term mortality in AIDS-associated Pneumocystis carinii pneumonia.

BACKGROUND: Since 1990, corticosteroids have been recommended as adjunctive therapy for patients with AIDS-associated Pneumocystis carinii pneumonia (PCP) and respiratory failure. We hypothesized that the natural course of AIDS-associated PCP has changed in the era of adjunctive corticosteroid therapy. OBJECTIVE: To study variables obtained on hospital admission for possible prognostic value of short-term (3-month) outcome of PCP. DESIGN AND PATIENTS: Prospective observational study of 176 consecutive HIV-1-infected individuals with PCP between 1990 and 1999. METHOD: Cox proportional-hazards regression models. RESULTS: Univariate analysis showed that age, one or more prior episodes of PCP, use of antimicrobial therapy other than trimethoprim-sulfamethoxazole (TMP-SMZ), use of PCP prophylaxis at diagnosis, and culture of cytomegalovirus (CMV) in BAL predicted progression to death within 3 months. After adjustment, age (relative risk [RR], 4.1; 95% confidence interval [CI], 1.8 to 9.3), initial antimicrobial therapy other than TMP-SMZ (RR, 3.1; 95% CI, 1.2 to 8.5), use of PCP prophylaxis (RR, 5.6; 95% CI, 2.2 to 14.4), and culture of CMV in BAL fluid (RR, 2.7; 95% CI, 1.3 to 5.6) remained independent predictors of a poor outcome. In contrast, neither PO(2) nor serum lactate dehydrogenase, which in earlier studies were identified as prognostic markers, were predictors of mortality. CONCLUSION: Age, initial anti-PCP therapy, use of PCP prophylaxis, and BAL CMV status may be useful predictors of outcome of PCP in patients treated in the era of adjunctive corticosteroid therapy.

Neopterin and interleukin-8--prognosis in alcohol-induced cirrhosis.

BACKGROUND: Neutrophil cytotoxity and activated macrophages have been implicated in the pathogenesis of alcohol-induced liver disease. The aim of this study was to relate plasma levels of neopterin, a marker of activation of the cellular immune system, and IL-8, a neutrophil chemotactic factor, with severity of liver disease and prognosis in patients with alcohol-induced cirrhosis. METHODS: Plasma concentrations of neopterin and IL-8 were assessed in 81 patients with alcohol-induced cirrhosis admitted to the Department of Medicine B, Bispebjerg Hospital, Copenhagen, Denmark, and in 16 healthy controls. After a median follow-up period of 5 years, mortality and death causes were registered. The patients were divided into groups according to the major contributing cause of death: infection, upper gastrointestinal bleeding or hepatic coma. RESULTS: Neopterin and IL-8 levels were increased in the cirrhosis patients, but not significantly related to Child-Pugh classification. Five-year mortality was 67%. High neopterin levels (>upper quartile) were an independent predictor of death (p=0.01, Log rank and p<0.02, Cox). High IL-8 levels (>upper quartile) were of no significant prognostic value for overall mortality. Causes of death related mortality were as follows (Log rank): Neopterin; p=0.009, p=0.84 and p=0.94, and IL-8; p=0.36, p=0.002 and p=0.27, respectively, according to infection, bleeding and coma as causes of death. CONCLUSIONS: Neopterin and IL-8 plasma levels are raised in patients with alcohol-induced cirrhosis, and are predictive of mortality associated with infections and upper gastrointestinal bleeding, respectively.

Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia.

BACKGROUND: Sulpha drugs are widely used for the treatment and long-term prophylaxis of Pneumocystis carinii pneumonia (PCP) in HIV-1-infected individuals. Sulpha resistance in many microorganisms is caused by point mutations in dihydropteroate synthase (DHPS), an enzyme that is essential for folate biosynthesis. We assessed whether mutations in the DHPS gene of P. carinii were associated with exposure to sulpha drugs and influenced outcome from PCP. METHODS: We studied bronchoalveolar samples collected in 1989-99 from a prospective cohort of HIV-1-infected patients who had PCP. In 144 patients with 152 episodes of PCP, we analysed portions of DHPS using PCR and direct sequencing. The relation between survival, P. carinii DHPS mutations, and other predictors of treatment failure was assessed by Kaplan-Meier and multivariate Cox regression analysis. FINDINGS: P. carinii DHPS mutations were found in 31 (20.4%) of 152 PCP episodes. 3-month survival was significantly lower in patients infected with mutant P. carinii DHPS strains than in those with wild-type strains (p=0.002). After adjustment for other prognostic variables, presence of DHPS mutations remained the most important predictor of mortality (hazard ratio 3.1 [95% CI 1.2-8.1]). DHPS mutations were significantly more common in patients who had previous exposure to sulpha drugs (18 of 29 [62%]) than in those who had no exposure (13 of 123 [10.5%]; p<0.0001). A significant increase with time in the rate of DHPS mutations (p=0.01 for trend) was closely correlated with the rate of previous or current use of sulpha drugs as chemoprophylaxis. INTERPRETATION: Mutations in DHPS are associated with impaired prognosis in PCP, and may develop as a result of exposure to sulpha drugs.

Pneumocystis carinii pneumonia in HIV-infected patients: effect of steroid therapy on surfactant level.

Previous studies have suggested alterations in pulmonary surfactant lipid in the setting of Pneumocystis carinii pneumonia in HIV-infected patients. Because pulmonary surfactant lipid is composed of a variety of lipid products and because other phospholipids might be present in bronchoalveolar lavage (BAL) lipid determinations, a single molecular species of phospholipid which comprises a substantial portion of the surfactant lipid fraction, dipalmitoyl phosphatidylcholine (DPPC), was measured by capillary column gas chromatography in BAL samples taken at the time of the diagnosis of P. carinii pneumonia, and 10 days after treatment for P. carinii pneumonia. DPPC was measured at day 0 and day 10 in seven patients who had been randomized to receive methylprednisolone adjuvant therapy for P. carinii pneumonia and in six patients who had been randomized to not receive methylprednisolone therapy. The level of DPPC in BAL from all patients at day 0 was 0.49 +/- 0.06 microgram ml-1 BAL. This level is significantly lower that the level of DPPC determined in BAL from five normal volunteers 2.48 +/- 0.40 micrograms ml-1. At day 0, the BAL level of DPPC in patients treated with methylprednisolone was not different from the BAL level of DPPC in patients not treated with methylprednisolone. By day 10 of therapy for P. carinii pneumonia, BAL levels of DPPC in all patients had increased to 1.05 +/- 0.19 micrograms ml-1 BAL. At day 10 DPPC levels in the methylprednisolone treated group were not different from the group not treated with methylprednisolone. We conclude that in HIV-infected patients, lung surfactant lipid is reduced in the setting of P. carinii pneumonia. The lipid levels return toward normal levels with treatment. Adjuvant therapy with corticosteroids does not alter the rate of recovery of surfactant lipid levels at least after 10 days of therapy.

Pneumocystis carinii major surface glycoprotein induces interleukin-8 and monocyte chemoattractant protein-1 release from a human alveolar epithelial cell line.

BACKGROUND: The major surface glycoprotein (MSG) is an abundant, immunogenic glycoprotein located on the surface of Pneumocystis carinii. Little is known about the proinflammatory effects of MSG. DESIGN: We have investigated the effect of human MSG on the secretion of the chemokines interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) from an alveolar epithelial cell line (A549). RESULTS: Incubation of A549 cells with MSG in concentrations from 0.4 to 10 microg mL-1 for 24 h caused dose-dependent increases in IL-8 release (3.4-fold above control, P < 0.01). Time course experiments showed increases in IL-8 release at 4 h, 8 h and 24 h compared with control cultures (all P < 0.01). There was a minor (13%) dose- and time-related increase in MCP-1 release at 24 h (P = 0.02). Co-incubation of MSG with mannan or beta-glucan decreased IL-8 release by 48% and 42% respectively, suggesting that MSG stimulates A549 cells in part through carbohydrate moieties. Dexamethasone significantly inhibited MSG-induced IL-8 release in concentrations of 10-6-10-8 mol L-1 compared with control experiments (P < 0.01). Ribonuclease protection assays for steady-state IL-8 mRNA showed that increases in response to MSG stimulation occurred by 4 h and persisted throughout 8 h of stimulation. CONCLUSION: These findings suggest that MSG can alter alveolar epithelial cytokine release and may be capable of modulating the local inflammatory response in this manner.

Does European or non-European origin influence health care and prognosis for HIV patients in Europe? The EuroSIDA Study Group.

BACKGROUND: Previous studies, especially in North America, have shown that socio-economic factors may influence the prognosis for patients with HIV. This study was performed in order to determine if European or non-European origin influence provision of health-care and survival among HIV patients in Europe. METHODS: Fifty HIV clinics in 17 European countries are involved in a European prospective, observational multicentre study. In total, 7230 consecutive patients with HIV attending a routine clinic visit were included in the study. Data on demographics, treatment and laboratory results were collected at time of recruitment into the study and thereafter every 6 months. RESULTS: The median CD4+ lymphocyte count at AIDS diagnosis was 60/mm3, and was similar for all ethnic groups (P = 0.87, Kruskall-Wallis test). The median terminal CD4+ lymphocyte count was 17/mm3 and, again, there was no significant difference between continents of origin (P = 0.35, Kruskall-Wallis test). Antiretroviral drugs were initiated at similar median CD4+ lymphocyte counts and there was no statistically significant difference in survival after a diagnosis of AIDS. CONCLUSIONS: AIDS was diagnosed at the same level of immunodeficiency independent of European or non-European origin and antiretroviral drugs were provided at similar levels of immunodeficiency. No differences in survival depending on continent of origin was found. In spite of these encouraging findings concerns remain that belonging to an ethnic minority can be an obstacle in getting into contact with treatment facilities and thus benefiting from developments in the management of HIV.

Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group.

BACKGROUND: The introduction of combination antiretroviral therapy and protease inhibitors has led to reports of falling mortality rates among people infected with HIV-1. We examined the change in these mortality rates of HIV-1-infected patients across Europe during 1994-98, and assessed the extent to which changes can be explained by the use of new therapeutic regimens. METHODS: We analysed data from EuroSIDA, which is a prospective, observational, European, multicentre cohort of 4270 HIV-1-infected patients. We compared death rates in each 6 month period from September, 1994, to March, 1998. FINDINGS: By March, 1998, 1215 patients had died. The mortality rate from March to September, 1995, was 23.3 deaths per 100 person-years of follow-up (95% CI 20.6-26.0), and fell to 4.1 per 100 person-years of follow-up (2.3-5.9) between September, 1997, and March, 1998. From March to September, 1997, the death rate was 65.4 per 100 person-years of follow-up for those on no treatment, 7.5 per 100 person-years of follow-up for patients on dual therapy, and 3.4 per 100 person-years of follow-up for patients on triple-combination therapy. Compared with patients who were followed up from September, 1994, to March, 1995, patients seen between September, 1997, and March, 1998, had a relative hazard of death of 0.16 (0.08-0.32), which rose to 0.90 (0.50-1.64) after adjustment for treatment. INTERPRETATION: Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the beginning of 1998 were less than a fifth of their previous level. A large proportion of the reduction in mortality could be explained by new treatments or combinations of treatments.

YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils.

YKL-40, also called human cartilage glycoprotein-39 (HC gp-39), is a member of family 18 glycosyl hydrolases. YKL-40 is secreted by chondrocytes, synovial cells, and macrophages, and recently it has been reported that YKL-40 has a role as an autoantigen in rheumatoid arthritis (RA). The function of YKL-40 is unknown, but the pattern of its expression in normal and disease states suggests that it could function in remodeling or degradation of the extracellular matrix. High levels of YKL-40 are found in synovial fluid from patients with active RA. Neutrophils are abundant in synovial fluid of patients with RA, and the cells are assumed to play a role in joint destruction in that disorder. Therefore, we examined whether neutrophils are a source of YKL-40. YKL-40 was found to colocalize and comobilize with lactoferrin (the most abundant protein of specific granules) but not with gelatinase in subcellular fractionation studies on stimulated and unstimulated neutrophils. Double-labeling immunoelectron microscopy confirmed the colocalization of YKL-40 and lactoferrin in specific granules of neutrophils. Immunohistochemistry on bone marrow cells showed that neutrophil precursors begin to synthesize YKL-40 at the myelocyte-metamyelocyte stage, the stage of maturation at which other specific granule proteins are formed. Assuming that YKL-40 has a role as an autoantigen in RA by inducing T cell-mediated autoimmune response, YKL-40 released from neutrophils in the inflamed joint could be essential for this response. In RA and other inflammatory diseases, YKL-40 released from specific granules of neutrophils may be involved in tissue remodeling or degradation.

Chemokine receptor CCR2b 64I polymorphism and its relation to CD4 T-cell counts and disease progression in a Danish cohort of HIV-infected individuals. Copenhagen AIDS cohort.

We have investigated the role of the recently described mutation in CCR2b named 64I in relation to HIV resistance, CD4 T-cell counts, and disease progression in Danish individuals by polymerase chain reaction (PCR)-based methods as well as sequenced full-length CXCR4 and CCR5 genes from HIV-infected long-term nonprogressors for possible mutations. In total, 215 Danish individuals were analyzed for 64I allele frequency; disease progression was followed in 105 HIV-1-positive homosexual Danish men from their first known positive HIV-1 test result and up to 11 years. In 87 individuals, the CD4 T-cell count was monitored closely. We found no significant difference in 64I allele frequency between HIV-1-seropositive persons (0.08), high-risk HIV-1-seronegative persons (0.11), and blood donors (0.06). No significant difference was observed in annual CD4 T-cell decline, CD4 T-cell counts at the time of AIDS, in AIDS-free survival as well as survival with AIDS, between 64I allele carriers and wild-type individuals. Among 9 long-term nonprogressors, 2 carried the 64I allele, while none of 9 fast progressors carried the 64I allele. However, this was not significantly different (p=.47). Long-term nonprogression could not be explained by CXCR4 polymorphism or other polymorphisms in the CCR5 gene than the CCR5delta32 allele. Furthermore, we were not able to detect any significant independent effect of the 64I allele on development to AIDS, overall survival, and annual CD4 T-cell decline in this cohort.

Rapid loss of specific antibodies after pneumococcal vaccination in patients with human immunodeficiency virus-1 infection.

Pneumococcal infections are frequently observed in patients with human immunodeficiency virus (HIV) infection and active immunization has been recommended as prophylaxis in this patient group. We studied 103 out-patients with asymptomatic or mildly symptomatic HIV infection with respect to specific IgG and IgG2 pneumococcal antibodies before and after vaccination with a 23-valent pneumococcal polysaccharide vaccine. A significant increase ( > 2-fold) in IgG and IgG2 antibody levels was observed after 1 month in 69/103 patients (67%) with no correlation with the CD4 cell count at the time of vaccination. The response rate was not influenced by concurrent treatment with anti-retroviral monotherapy, or by age or gender. After immunization a strong correlation between IgG and IgG2 anti-pneumococcal antibodies was demonstrated. Nevertheless, 12 months after vaccination the specific antibody titres were not significantly different from pre-vaccination values. In conclusion, antibodies induced by pneumococcal vaccination in patients with HIV infection have a short duration. This raises the question as to whether vaccination will have any impact on clinical end-point in this group of patients.

Complete histological regression of Kaposi's sarcoma following treatment with protease inhibitors despite persistence of HHV-8 in lesions.

There is no current curative treatment for HIV-related Kaposi's sarcoma. The identification of human herpesvirus-8 as a possible aetiological agent suggests potential efficacy of anti-viral agents. We report here on the complete histological remission of Kaposi's sarcoma following treatment with protease inhibitors, even in patients with limited virological response and persistence of HHV-8.

Regional differences in use of antiretroviral agents and primary prophylaxis in 3122 European HIV-infected patients. EuroSIDA Study Group.

Little is known about how widely HIV-related drugs are used outside controlled clinical trials. We therefore assessed factors associated with use of antiretroviral (ARV) therapy and primary prophylactic regimens to prevent HIV-associated opportunistic infections. Baseline data from a prospective study from May to August 1994, on 3122 consecutive HIV infected patients with a CD4 count <500 cells/microl, followed in 37 centers from 16 European countries, were analyzed. Two thousand and twenty patients (65%) were receiving at least 1 ARV drug at the time of the study. ARV therapy was more frequently used among patients from southern and central Europe as compared with patients from northern Europe, especially among patients with CD4 counts >200 cells/microl (73%, 57%, and 42%, respectively, p < 0.0001). Of patients on ARV therapy, 34% received open-label combination therapy. This proportion was higher in central Europe compared with other regions (27%, 50%, and 31% for southern, central, and northern Europe, respectively, p < 0.0001). Primary prophylaxis against Pneumocystis carinii pneumonia (PCP) was used by 85% of patients with a CD4 count <200 cells/microl, without marked regional differences. In patients without esophageal candidiasis or other invasive fungal infections, antifungal drugs were far less frequently used in patients from southern and central Europe compared with patients from northern Europe (10%, 10%, and 25%, respectively, p < 0.0001). Only 5% of patients with a CD4 count <100 cells/microl received rifabutine as primary prophylaxis against nontuberculous mycobacterioses. ARV and antifungal therapies are used differently in different parts of Europe, whereas primary PCP prophylaxis is uniformly administered to most at-risk patients. U.S. recommendations on the use of antimycobacterial prophylaxis have not been implemented in Europe.

The major surface glycoprotein of Pneumocystis carinii induces release and gene expression of interleukin-8 and tumor necrosis factor alpha in monocytes.

Recent studies suggest that interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) may play a central role in host defense and pathogenesis during Pneumocystis carinii pneumonia. In order to investigate whether the major surface antigen (MSG) of human P. carinii is capable of eliciting the release of IL-8 and TNF-alpha, human monocytes were cultured in the presence of purified MSG. MSG-stimulated cells released significant amounts of IL-8 within 4 h, and at 20 h, cells stimulated with MSG released 45.5 +/- 9.3 ng of IL-8/ml versus 3.7 +/- 1.1 ng/ml for control cultures (P = 0.01). In a similar fashion, MSG elicited release of TNF-alpha. Initial increases were also seen at 4 h, and at 20 h, TNF-alpha levels reached 6.4 +/- 1.1 ng/ml, compared to 0.08 +/- 0.01 ng/ml for control cultures (P < 0.01). A concentration-dependent increase in IL-8 and TNF-alpha secretion was observed at 20 h with 0.2 to 5 microg of MSG/ml (P < 0.01). Secretion of IL-8 and TNF-alpha from MSG-stimulated monocytes at 20 h was inhibited by 60 and 86%, respectively, after coincubation with soluble yeast mannan (P = 0.01). With an RNase protection assay, increases in steady-state mRNA levels for IL-8 and TNF-alpha were detectable at 4 h. These data show that recognition of MSG by monocytes involves a mannose-mediated mechanism and results in the release of the proinflammatory cytokines IL-8 and TNF-alpha.