Human interleukin-6 is in vivo an autocrine growth factor for human herpesvirus-8-infected malignant B lymphocytes

Human interleukin-6 (hIL-6) acts as a growth factor in several human B lymphoid cancers. As human herpesvirus-8 (HHV-8) encodes for a viral IL-6 (vIL-6), the viral cytokine may be responsible for several manifestations of HHV-8-related disorders. Using an anti-hIL-6 mAb (B-E8) which does not recognize vIL-6, we investigated the involvement of the human cytokine in the proliferation of HHV-8-positive primary effusion lymphoma (PEL) cells. In vitro, 5/5 PEL cell lines produced hIL-6 (4 to 1,200 pg/ml). The EBV- HHV-8+ cell line (BCBL-1) was adapted to grow in SCID mice. hIL-6 was detected in the serum of mice with grafts, as well as human soluble CD138 (sCD138) and human IL-10 (hIL-10). The serum level of these mediators increased with tumor progression. The effect of treatment with the B-E8 mAb on the tumor progression and survival was evaluated. This treatment significantly slowed down the tumor development: on day 54, there were more mice with low levels of sCD138 and hIL-10 in the treated group than in controls (p = 0.03 and 0.02, respectively); treatment also delayed death (median date of death was day 65 for control mice and day 84 for anti-hIL-6 mAb-treated mice; p < 0.02). Thus, hIL-6 is expressed in addition to vIL-6 in HHV-8-positive malignant B lymphocytes, and the viral cytokine does not totally substitute for human IL-6 in promoting tumor progression.     

Cytokine detection in HIV-1/HHV-8 co-infected subjects

In a previous work we have evaluated some immunologic and haematologic parameters of HIV-1 positive subjects co-infected with HHV-8. A worsening of these values were generally described in these patients as compared with those HIV-1 positive, but negative for HHV-8. Now we have studied the influence of HHV-8 co-infection of HIV-1 positive subjects on the production of some cytokines to make clear the question of its role in the immuno-deregulation of the above-mentioned subjects. In particular we have analysed serum levels of IL-4 and IL-10, Th2 type T cells cytokines, IFN-gamma, an indirect marker of Th1 cells activation and IL-18, a cytokine produced by monocytic-macrophagic cells, which is able to induce IFN-gamma production and Th1 T lymphocytes activation. No significant differences were found as regards the IFN-gamma serum levels (92.1 +/- 24.3 pg ml(-1) in the case of HIV-1 positive/HHV-8 negative subjects and 96.0 +/- 17.4 pg ml(-1) in those HIV-1 positive/HHV-8 positive). In healthy subjects the mean level of this cytokine was 17.6 +/- 5.2 pg ml(-1) (significant difference with both the former values at p < 0.001). Moreover IL-4 and IL-10, which were undetectable in healthy individuals, showed the following values in HIV-1 positive/HHV-8 negative subjects: 31.9 +/- 2.7 pg ml(-1) and 119.8 +/- 85.1 pg ml(-1) respectively and in HIV-1 positive/HHV-8 positive subjects: 30.4 +/- 4.8 pg ml(-1) and 69.4 +/- 65.3 pg ml(-1) (not significant differences). In contrast IL-18 reached a mean level of 1001.2 +/- 360.5 pg ml(-1) in HIV-1 positive/HHV-8 negative subjects, but showed a significant reduction in HIV-1 positive/HHV-8 positive subjects (737.6 +/- 284.3 pg ml(-1) --> p < 0.05) and presented very low levels in healthy individuals (21.3 +/- 30.3 pg ml(-1)). Moreover a significant correlation (-0.984 --> p < 0.001) was noticed between IL-18 reduction in HIV-1 positive subjects co-infected with HHV-8 and the degree of positivity of HHV-8. These data suggest that HHV-8 co-infection has no influence on the switch Th1 --> Th2 in HIV-1 positive subjects, but is able to reduce IL-18 production, useful for Th1 subset restoration.     

Prevalence of Human Herpesvirus 6 Variants A and B in Patients with Chronic Fatigue Syndrome

Peripheral blood mononuclear cells collected from 13 patients with chronic fatigue syndrome and 13 healthy controls were analyzed for the presence of human herpesvirus 6 (HHV-6) DNA by variant-specific polymerase chain reaction and dot blot hybridization. HHV-6 DNA was detected in 7 of 13 (53%) patients, and of those 7 patients, 4 were positive for HHV-6 variant A DNA and 3 were for variant B. No HHV-6 DNA was detected in the controls. Serum antibody titers to the late antigen and antibody prevalence to the early antigen of HHV-6 were significantly higher in the patient group. These results suggest active replication of HHV-6 in patients with chronic fatigue syndrome.     

代谢综合症患者血清IL-18 水平变化及临床意义

目的:研究血清IL-18与亚代谢综合症(亚MS)、代谢综合症(MS)的关系,探讨生活方式改变(TLC)后IL-18及相关标记物的变化及其临床意义。方法:16例对照组,14例亚MS组,34例MS组;采用自动生化仪测定空腹血脂水平;采用乳胶增强免疫比浊法检测hs-CRP水平;采用ELISA法检测受试者血清IL-18、IL-6和脂联素水平。结果:MS患者血清IL-18水平与腰围有明显相关性(rs=0.45,P<0.01);与亚MS组比较,MS组IL-18水平显著升高(P<0.01);与正常组比较,MS组患者的腰围、体重指数、hs-CRP、IL-6及IL-18显著升高(P<0.05)。TLC后体重减轻5%,MS患者IL-18、IL-6、hs-CRP水平显著降低(P<0.01),脂联素水平显著升高(P<0.01)。结论:IL-18可作为亚MS和MS预测指标,鉴别亚MS与MS,其含量的变化对病情进展的程度及疗效的判定有重要意义。     

IL-18 is redundant in T-cell responses and in joint inflammation in antigen-induced arthritis

IL-18 is an important cofactor in Th1 immune responses and it has additional roles in inflammation. Recent reports suggest the contribution of IL-18 to immune responses may vary between mouse strains and immune contexts. We investigated the contribution of IL-18 to T-cell activation and joint inflammation in Ag-induced arthritis (AIA) in C57Bl/6 mice. AIA and cutaneous delayed-type hypersensitivity (DTH) reactions were induced in wild-type (WT) and IL-18-/- C57Bl/6 mice, and Ag-specific T-cell proliferation and IFN-gamma and IL-4 production were measured. The humoral immune response was measured as serum antibody to the disease-initiating Ag, methylated BSA (mBSA). Splenocyte production of IL-6 was measured by ELISA. To confirm the dependence of this model on Th1-cell-mediated immunity, IL-12p40-/- mice were similarly studied. WT mice developed synovitis, joint effusion, cartilage destruction and bone damage associated with induction of DTH, and in vitro Ag-specific T-cell proliferation and IFN-gamma production. Unexpectedly, IL-18-/- mice developed AIA and indices of T-cell activation were similar to those of WT mice. In contrast, IL-12p40-/- mice did not develop AIA, DTH or T-cell activation. WT and IL-18-/- mice, but not IL-12p40-/- mice, developed significantly increased serum antibody to mBSA compared with naive controls. WT and IL-18-/- splenocytes produced high levels of IL-6, whereas IL-12p40-/- cells had significantly lower IL-6 production compared with both. In conclusion, IL-18 is redundant both as a Th1 response cofactor and inflammatory cytokine, whereas IL-12p40-/- is a key cytokine, in AIA in C57Bl/6 mice.     

Effect of interferon-beta and atorvastatin on Th1/Th2 cytokines in multiple sclerosis

Beneficial effects by both interferon-beta and statin treatment in patients with multiple sclerosis (MS) may be linked to interference with the Th1/Th2 cytokine balance. We determined patterns of Th1/Th2 cytokines (interleukin (IL)-1beta, IL-2, IL-6, IL-12p70, tumor-necrosis factor (TNF)-alpha and interferon-gamma, and IL-4, IL-5 and IL-10, respectively) in the serum of patients with relapsing-remitting MS treated with 250microg interferon-beta 1b or with interferon-beta plus 40mg atorvastatin. In treatment na?ve patients with MS, a trend for lower TNF-alpha serum levels compared to controls was detected (P=0.08). Interferon-beta treatment increased TNF-alpha levels, while a trend for lowering of IL-5 serum levels was found (P=0.07). Addition of atorvastatin raised IL-12p70 serum levels (P<0.05). Mean levels of two Th2 cytokines (IL-4, IL-10) showed a non-significant increase after addition of atorvastatin. We conclude that interferon-beta and atorvastatin exert divergent action on Th1/Th2 serum cytokines levels in MS. Supplemental atorvastatin might promote a Th1-type response by raising IL-12p70. Further studies are required to support a Th2 cytokine shift by atorvastatin in patients with MS.     

Correlation between human herpesvirus 6 and 7 infections after living related liver transplantation

Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) are closely related to each other. Interaction between the two viruses at the time of primary HHV-7 infection is suggested by in vivo and in vitro studies. However, interaction between the two viruses in organ transplant recipients has not been analyzed. We analyzed serially collected plasma samples obtained from 40 living related liver transplant recipients by serological assay (indirect immunofluorescence assay, IFA) and polymerase chain reaction (PCR). Significant increase or seroconversion of HHV-6 IgG and HHV-7 IgG antibody titers were observed in 45% and 58% of recipients respectively. Positive rate of IgM HHV-6 antibody increased up to 35% at 4 weeks after transplantation. However, no remarkable peak in the positive rate of HHV-7 IgM antibody was demonstrated. HHV-6 and HHV-7 DNA were detected in plasma in 15 (38%) and 16 (40%) of the 40 recipients respectively. HHV-6 DNA was detected in 10 (26%) of the 38 recipients at 2 weeks after transplantation. The positive rate of the virus genome in plasma gradually decreased after that time. HHV-7 DNA was detected in 5 (14%) of the 37 recipients at 2 weeks after transplantation; no obvious peak in the positive rate of HHV-7 DNA was demonstrated. Antibody responses involving both HHV-6 and HHV-7, including either a significant increase in IgG antibody titers or positive identification of IgM antibody were observed in 17 (43%) of the 40 recipients. Thirteen out of the 17 recipients demonstrated concurrent antibody response against both viruses. HHV-7 antibody response preceded the HHV-6 antibody response in 2 of the remaining 4 recipients, whereas the opposite was true in the other 2 recipients. Both HHV-6 and HHV-7 DNA were detected in 7 (18%) of the 40 recipients. In 4 of those 7 recipients, DNA from both viruses was concurrently detected, 3 of whom had HHV-7 DNA repeatedly detected after first detection of the virus DNA. The detection of HHV-7 DNA preceded the detection of HHV-6 DNA in 2 recipients, whereas HHV-6 DNA appeared first in 1 recipient.     

Prevalence of antibody to human herpesvirus 6 in women and children

The antibody prevalence to human herpesvirus 6 (HHV-6) was compared between pregnant women and control women of similar ages in Thailand. No significant difference was detected in the antibody positive rate and antibody titers between both groups. The antibody titers in sera collected from pregnant women at 1st and 3rd trimester remained unchanged. Next, the antibody prevalence in infants were examined and the positive rate decreased until 3 months and started to increase from 6 months after birth. The present results suggest that the reactivation of HHV-6 might not occur during pregnancy and this virus infects infants postnatally.     

Human herpesvirus 6 infection of CD4+ T-cell subsets

The immune system includes CD4+ regulatory T (T reg) cells that play a role in self-tolerance and demonstrate functional variations that govern immune responses. HHV-6 is an important immunosuppressive virus that completely replicates in vivo and in vitro in only CD4+ T cells. However, there have been no reports of the specific T-cell subpopulation that permits the replication of this virus. Here, we evaluated the infectivity of HHV-6 to specific T-cell populations such as CD4+CD25 high, which includes the majority of T reg cells, and CD4+CD25(-). These cells were isolated from peripheral blood and then expanded. The expanded cell fractions were then infected with the HHV-6 variant B strain, and the spreads of infected cells were evaluated by immunofluorescence. Viral growth was also quantified by real-time PCR. The effects of virus infection on cytokine production from these T-cell subsets were examined using ELISA. Our results revealed that both these fractions permitted complete HHV-6 replication. Virus infection enhanced the production of both Th1- and Th2-type cytokines from CD4+CD25(-) T cells; however, only Th2-type cytokine release was augmented from viral-infected CD4+CD25 high T cells. Further, while virusinfected CD4+CD25 high T cells shift their antiviral immunity toward Th2 dominance by producing IL-10, the role of virus-infected CD4+CD25(-) T cells remains obscure.     

Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients

The alpha(4) integrin antagonist natalizumab was shown to be effective in patients with immune-mediated disorders but was unexpectedly associated with JC polyomavirus associated progressive multifocal leukoencephalopathy (PML) in two multiple sclerosis (MS) and one Crohn's disease patients. Impaired immune surveillance due to natalizumab treatment may have contributed to the JCV reactivation. As HHV-6 has been suggested to play a role in MS, we asked whether this virus could also have been reactivated during natalizumab therapy. Matched sera and CSF from a limited set of MS patients treated with and without natalizumab were examined for evidence of HHV-6. In addition, we also superinfected a persistent JC virus infected glial cell with HHV-6A to determine if JC virus can be increased. Elevated serum HHV6 IgG and HHV-6A DNA was detected in the CSF of a subset of patients but not controls. We confirmed that superinfection with HHV-6 of a JC virus infected glial cells increased expression of JCV. These results support the hypothesis that treatment with natalizumab may be associated with reduced immune surveillance resulting in reactivation of viruses associated with MS pathogenesis.     

IgM neutralizing antibody responses to human herpesvirus-6 in patients with exanthem subitum or organ transplantation.

The assay for detecting IgM neutralizing (NT) antibody activity to human herpesvirus-6 (HHV-6) was developed by using pretreatment of blood sample with staphylococcal protein A. The activity was mostly present in IgM fractions of serum but not in IgA fractions separated by ultracentrifugation. The assay was used for seroepidemiological studies for HHV-6 infection. In primary HHV-6 infection, IgM NT antibodies appeared 5 to 7 days after onset of exanthem subitum, reached maximum titers at 2 to 3 weeks, and tended to decline to undetectable levels after 2 months. In contrast, reactivation of HHV-6 observed in organ transplants showed somewhat greater degree of IgM NT antibody responses that persisted for 2 to 3 months and became undetectable 5 to 6 months after transplantation. The level and persistence of NT antibody titers measured by the conventional method was generally greater than those of the IgM titers. The prevalence of the IgM NT antibodies was examined in healthy individuals. The antibody was first detected at 4 to 7 months of age (5%), reached maximum level at 8 to 11 months (40%), and was detectable by 4 to 6 years (17%). A few (4 to 5%) of adolescents and adults were positive for the antibody.     

Chronic infections and genetic factors in the development of ischemic stroke

The aim of this study was to examine whether chronic infections and genetic factors of the host play roles in the pathophysiology of acute noncardioembolic ischemic stroke. Blood samples from 59 subjects with ischemic stroke and 52 control patients were investigated by nested PCR for the presence of C. pneumoniae DNA, HCMV DNA and enterovirus RNA, by ELISA for the levels of antibodies to C. pneumoniae, HCMV, HSV, HHV-6, EBV and the inflammatory chemokine IL-8, and by PCR for promoter polymorphism of the IL-8 and CD14 host genes. Associations of stroke with the HCMV IgG and HSV-1 IgA antibody levels were observed. No association of stroke was detected with the presence of C. pneumoniae, HCMV or enterovirus nucleic acids in the peripheral blood, C. pneumoniae IgM, IgG and IgA, the HSV IgG, the EBV IgG, or HHV-6 IgG antibody levels, the pathogen burden, the IL-8 or CD14 promoter polymorphisms, or with the serum levels of IL-8 in the overall study population. These results are consistent with the hypothesis that certain pathogens are involved in the development of ischemic stroke.     

Cytokine responses to acute and chronic exercise in multiple sclerosis.

Regular exercise reduces functional loss associated with multiple sclerosis (MS). However, the impact of exercise on inflammatory mediators associated with disease activity remains relatively unexplored. The purpose of this study was to determine whether ambulatory MS subjects would respond similarly to aerobic cycle training compared with matched controls on circulating immune variables, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Eleven MS and 11 non-MS control subjects (8 women and 3 men in both groups) matched in age, height, body mass, body fat, and peak O(2) uptake completed the study. Subjects completed 30 min of cycle ergometry at 60% of peak O(2) uptake, 3 day/wk for 8 wk. Plasma cytokine concentrations were determined before and after exercise at weeks 0, 4, and 8. MS and control subjects showed a similar cytokine responses to exercise. IL-6 at rest tended to decrease (P = 0.08) with training in both groups. Resting plasma TNF-alpha tended to be higher in MS compared with controls throughout the study (P = 0.08). MS subjects showed elevated resting TNF-alpha in MS at the end of the 8-wk program (P = 0.04), whereas resting TNF-alpha remained unchanged in controls (P > 0.05). Resting plasma IFN-gamma at rest was elevated in MS subjects (P = 0.008) and unchanged in controls at the end of the intervention (P > 0.05). The response of plasma IL-6, TNF-alpha, and IFN-gamma after a single bout of exercise was similar between MS and control subjects (P > 0.05). Additional research to understand the impact of exercise on immune variables in MS is warranted.     

乳腺癌患者血清内IL-6 和CCL-18表达及其与临床病理因素的关系

目的:探究乳腺癌患者血清内白细胞介素-6(IL-6)和趋化因子配体-18(CCL-18)表达水平及其与临床病理因素的关系。方法:本研究于2014年4月~2015年4月期间,选择我院收治31例乳腺癌患者(乳腺癌组)、29例良性肿瘤患者(良性肿瘤组)与30例健康体检者(对照组)为研究对象,采用酶联免疫吸附试验(ELISA)法测定所有研究对象的血清IL-6与CCL-18水平,采用免疫组化法检测患者的临床病理参数。结果:乳腺癌组患者血清IL-6和CCL-18水平均显著高于良性肿瘤组和对照组,良性肿瘤组血清IL-6和CCL-18水平高于对照组,差异均有统计学意义(P0.05);血清IL-6S水平与雌激素受体(ER)、肿瘤增殖抗原(Ki67)、肿瘤TNM分期及淋巴转移存在关联(P0.05),血清CCL-18水平与Ki67与肿瘤TNM分期存在关联(P0.05)。结论:IL-6和CCL-18在乳腺癌患者内出现高表达,且均可预示患者肿瘤的发展恶化,影响预后。     

肿瘤坏死因子拮抗剂对强直性脊柱炎患者血清相关细胞因子变化的影响及其机制研究

目的:观察肿瘤坏死因子(TNF)拮抗剂对强直性脊柱炎(AS)患者血清中IL-6、IL-17、IL-21、IL-23、TNF-α、TGF-β1表达的影响,结合临床指标的变化探讨肿瘤坏死因子拮抗剂治疗AS的机制与疗效。方法:治疗组应用益赛普联合西乐葆,益赛普25 mg,皮下注射,连用8周,治疗前后评估晨僵VAS评分、腰背痛VAS评分、Bath强直性脊柱炎功能指数(BASFI)及血沉等指标,记录不良反应。用酶联免疫吸附法检测25例肿瘤坏死因子拮抗剂联合COX-2抑制剂治疗前、治疗第4周和治疗8周后AS患者血清中IL-6、IL-17、IL-21、IL-23、TNF-α、TGF-β1的表达情况,检测对照组(20例单独应用COX-2抑制剂的AS患者)治疗前、治疗后的细胞因子水平。结果:肿瘤坏死因子拮抗剂组患者血清中IL-6、IL-17、IL-23、TNF-α的表达在治疗第4周和治疗8周后较本组治疗前及对照组均有明显下降(P0.05);细胞因子IL-21、TGF-β1的表达水平较本组治疗前及对照组无明显降低(P0.05);对照组患者血清中IL-6、IL-17、IL-21、IL-23、TNF-α、TGF-β1的表达在治疗后较治疗前均无明显下降(P0.05);治疗组应用肿瘤坏死因子拮抗剂后较治疗前晨僵及腰背痛VAS评分、BASFI、血沉均显著改善(P0.05),临床疗效优良率为88.0%,对照组优良率为50.0%,有显著差异(P0.05),且治疗组不良反应轻微。结论:肿瘤坏死因子拮抗剂可能是通过降低AS患者血清中一系列细胞因子的表达水平,改善患者的免疫功能及临床症状,延缓了病程进展。但由于病例较少,肿瘤坏死因子拮抗剂联合COX-2抑制剂治疗AS患者的疗效需要在临床中进一步观察。     

Human acute lymphoblastic leukemia (ALL) blasts as accessory cells during T-cell activation: differences between patients in costimulatory capacity affect proliferative responsiveness and cytokine release by activated T cells

The ability of acute lymphoblastic leukemia (ALL) blasts to mediate costimulatory signals during T-lymphocyte activation was investigated in an experimental model in which monoclonal T-cell populations were stimulated with standardized activation signals (anti-CD3 and anti-CD28 monoclonal antibodies; phytohemagglutinin, PHA). Leukemia cells from 12 consecutive ALL patients with high peripheral blood blast counts were studied. Proliferative T-cell responses were detected for a majority of these patients when irradiated leukemia blasts were used as accessory cells during activation. T-cell cytokine release was also observed for most patients when using nonirradiated ALL accessory cells. Low or undetectable cytokine levels were usually observed for CD8+ clones, whereas the CD4+ clones often showed a broad cytokine response with release of interleukin-2 (IL-2), IL-4, IL-10, IL-13 and interferon gamma(IFN-gamma) in the presence of the ALL accessory cells. ALL blasts were also able to function as allostimulatory cells for normal peripheral blood mononuclear responder cells. However, both T-cell proliferation and cytokine release showed a wide variation between ALL patients. The accessory cell function of ALL blasts showed no correlation with the release of immunomodulatory mediators (IL-2, IL-10, IL-15) or the expression of any single adhesion/costimulatory membrane molecule (CD54, CD58, CD80, CD86) by the blasts. We conclude that for a majority of patients, native ALL blasts can mediate costimulatory signals needed for accessory cell-dependent T-cell activation, but differences in costimulatory capacity between ALL patients affects both the proliferative responsiveness and cytokine release by activated T cells.     

血清IL-6、miR-17-5p水平与卵巢癌患者化疗后生存期的相关性分析

目的:分析血清白细胞介素-6(IL-6)、微小RNA-17-5p(miR-17-5p)水平与卵巢癌患者化疗后生存期的相关性。方法:选取行手术治疗联合术后化疗的65例卵巢癌患者作为病例组,选取50名健康体检者作为对照组,选取50例良性卵巢疾病患者作为良性疾病组,对病例组患者术前及术后14d的血清IL-6、miR-17-5p水平进行检测和比较,对良性疾病组和对照组研究对象的血清IL-6、miR-17-5p水平进行检测和比较,对病例组患者进行随访,对其总生存期(OS)和无疾病进展生存期(PFS)进行观察和比较。结果:病例组患者血清IL-6、miR-17-5p表达水平显著高于良性疾病组,良性疾病组患者的血清IL-6、miR-17-5p表达水平显著高于对照组,各组之间的差异均有统计学意义(P0.05)。病例组患者术后14d血清IL-6、miR-17-5p表达水平较手术前显著下降,差异均有统计学意义(P0.05)。血清IL-6、miR-17-5p高表达的卵巢癌患者中TNM分期为Ⅲ~Ⅳ期的比例较高,差异均有统计学意义(P0.05)。血清IL-6、miR-17-5p高表达卵巢癌患者的OS和PFS明显短于血清IL-6、miR-17-5p低表达患者,差异均有统计学意义(P0.05)。血清IL-6和miR-17-5p同时呈现低表达的卵巢癌患者的OS和PFS水平最高,血清IL-6或miR-17-5p其中之一呈现高表达卵巢癌患者的OS和PFS水平居中,而血清IL-6和miR-17-5p同时呈现高表达的OS和PFS水平最低,差异均有统计学意义(P0.05)。结论:卵巢癌患者可表现为血清IL-6、miR-17-5p水平的显著升高,在手术治疗后,其水平会出现下降,术前较高的血清IL-6、miR-17-5p表达水平与较短的生存期和不良预后具有关联性,可作为预测患者预后的辅助指标。     

Elevated levels of circulating interleukin-18 in human immunodeficiency virus-infected individuals: role of peripheral blood mononuclear cells and implications for AIDS pathogenesis

Originally identified as the gamma interferon-inducing factor, interleukin-18 (IL-18) was rediscovered as a proinflammatory cytokine related to the IL-1 family of cytokines that plays an important role in both innate and adaptive immune responses against viruses and intracellular pathogens. Despite its importance in inducing and regulating immune responses, relatively little is known about its production in HIV infection. We report here significantly (P < 0.05) elevated levels of this cytokine in the sera of human immunodeficiency virus (HIV)-infected/AIDS patients compared to those of HIV-seronegative healthy persons. Surprisingly, the peripheral blood mononuclear cells (PBMC) from HIV-infected/AIDS patients were compromised in the ability to upregulate IL-18 gene expression and produce this cytokine with and without lipopolysaccharide (LPS) stimulation. A significant positive correlation (P < 0.05) existed between the concentration of IL-18 in serum and its production from PBMC of HIV-seronegative healthy individuals but not those of HIV-infected/AIDS patients. Furthermore, the patients' PBMC expressed relatively reduced levels of activated caspase-1 constitutively as well as in response to LPS stimulation. Our data suggest the involvement of transforming growth factor beta (TGF-beta) in suppressing IL-18 production from the patients' PBMC for the following reasons. (i) In in vitro studies it suppressed the production of IL-18 from PBMC. (ii) Its levels were significantly higher in the plasma of patients compared to that of control subjects. (iii) A significant negative correlation existed between the concentrations of TGF-beta in plasma and of IL-18 in serum of the patients. The elevated levels of IL-18 in the serum of HIV-infected individuals may contribute to AIDS pathogenesis, whereas its compromised production from their PBMC in response to stimuli may reduce their innate defense to opportunistic intracellular pathogens.