Production Of Immunoregulatory Cytokines Research Articles

Serum Interleukin-10 Level in Patients with Chronic Hepatitis B Infection

Background/Aims: Preferential production of immunoregulatory cytokines may play an important role in the pathogenesis of chronic hepatitis B. Patients with chronic hepatitis B infection were evaluated to determine whether serum interleukin-10 (IL-10) levels were changed and whether the degree of these changes in serum levels correlated with HBV DNA levels, histologic activity index (HAI) or serum aminotransferase levels (ALT). Methodology: 15 patients diagnosed of chronic hepatitis B (wild type) with raised ALT, 15 inactive HBsAg carriers, 15 healthy people with resolved acute hepatitis B, and 15 healthy controls without any hepatitis marker positivity were included in the study. Serum IL-10 levels were measured. The associations between liver pathology, HBV DNA and ALT levels were assessed. Result: IL-10 is elevated more in chronic hepatitis B with positive HBeAg and raised ALT in comparison to asymptomatic carrier, resolved acute hepatitis B and control. Conclusions: IL-10 production is increased in chronic hepatitis B patients with HBeAg positivity and raised ALT as compared to other groups ( p < 0.01). No correlation between HBV DNA, HAI or ALT could be established through this study. However, as IL-10 is increased in chronic hepatitis B infection with HBeAg positivity, the HBe antigen may be responsible for the raised IL-10 levels.

Chlamydia pneumoniae infection modulates cytokine production by human T lymphocytes and monocytes (43.11)

Abstract Continuous cell line cultures of human lymphocytes (MOLT-4) and monocytes (THP-1) were examined for production of immunoregulatory cytokines involved in immune responses to the intracellular opportunistic pathogen Chlamydia pneumoniae (Cp). Infection with Cp is widely prevalent and believed involved in chronic inflammatory diseases such as atherosclerosis and even neurodegenerative diseases like Alzheimer’s disease and multiple sclerosis. The results of this study showed that MOLT-4 and THP-1 cells were readily infected by Cp in vitro assessed by immunofluorescence microscopy for Cp lipopolysaccharide (LPS) and by real time RT-PCR for 16S rRNA expression. Stimulation of MOLT-4 cells with heat killed Cp (KCp) or Escherichia coli LPS (E. coli LPS) induced Th1 cytokines IFNγ and IL-12 and Th2 cytokine IL-10, but infection with viable Cp showed a dominant Th1 cytokine production. Cp infected THP-1 cells mainly produced IL-12 and enhanced TNFα and IL-10 production compared to cultures stimulated with KCp or E. coli LPS as a control. These results suggest that Cp infection modulates the immune response to a Th1 biased cytokine profile by T cells in addition to induction of TNFα by monocytes/macrophages. Such effects are likely involved in antibacterial immunity against Cp infection.

Anti-erythroblast autoimmunity in early myelodysplastic syndromes

Autoimmune phenomena, mainly directed against red blood cells are described in myelodysplastic syndromes (MDS), particularly early MDS, i.e. refractory anemia (RA) and RA with ringed sideroblasts (RARS). Dysregulation of apoptosis and immunoregulatory cytokines are thought to play a role in the pathogenesis of MDS. This work was aimed to investigate anti-erythroid autoimmunity in unstimulated and mitogen-stimulated peripheral blood and bone marrow cultures of 26 patients with early MDS (RA and RARS), and to relate its presence with apoptotic markers and cytokine production. Bone marrow cytokine production in culture supernatants, and caspase-3 and nuclear factor-kappaB activity in cell extracts were tested by enzyme-linked immunosorbent assays. Fourteen of the 26 (53.8%) patients showed the presence of autoantibodies in bone marrow cultures, whereas none displayed a positive direct antiglobulin test in peripheral blood cultures. Incubation of culture supernatants from positive patients with autologous CD45- enriched-cell suspensions showed that the autoimmune reaction was directed against autologous erythroblasts. These patients had mild signs of hemolysis and increased numbers of erythroblasts, compared with negative patients. Patients with anti-erythroblast autoimmunity displayed higher caspase-3 activity and lower tumor necrosis factor-alpha and interleukin-4 production than did negative patients. Half of the patients with early MDS showed autoimmunity against erythroblasts. This evidence might support a more rationale use of steroid therapy in these patients. The lower levels of cytokines in patients with anti-erythroblast autoimmunity are consistent with the suggested hypothesis that the autoimmune phenomena observed in MDS are probably initiated and perpetuated through alterations of pro-inflammatory and/or immunoregulatory cytokine production.

Mast cell, a promising therapeutic target in tubulointerstitial fibrosis

Tubulointerstitial fibrosis is a final common pathway to the eventual structural desolation of kidneys. However, the mechanism involved in this phenomenon is still poorly understood, and current therapies are ineffective or only marginally effective. Mast cell has a variety of physiological and pathological functions through the production of heparin, histamine, neutrophil chemoattractants, immunoregulatory cytokines, and mast cell-specific serine proteases tryptase and chymase. The survival and proliferation of mast cell are dependent upon stem cell factor. Presently, mast cells are known to participate in the pathogenesis of tubulointerstitial fibrosis in many kidney diseases. Several therapeutic approaches to inhibit mast cell activation have already demonstrated some clinical utility in tissue fibrosis or inflammatory diseases such as the use of mast cell stabilizers, inhibitors of tryptase or chymase, blockade of stem cell factor and anti-IgE therapy. We hypothesize that mast cell has a significant role in the progression of tubulointerstitial fibrosis, thus the treatment strategies based on mast cell appear to be promising in these conditions. Development of these novel therapeutic approaches will enable us to target any types of renal disease.

Increased killing activity and decreased cytokine production in NK cells in patients with primary biliary cirrhosis

Although the pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic, the immune system plays a key role in the initiation and subsequent development of pathology. Previous studies have indicated a critical role of the innate immune system. Importantly, natural killer (NK) cells are abundant in liver where they serve as sentinels of the immune system. In addition, NK cells have significant biologic activity based on their production of immunoregulatory cytokines. To address this issue, we have investigated several qualitative and quantitative activities of NK cells in patients with PBC as well as normal and liver diseased controls. We report herein a marked increase in the frequency and absolute number of blood and liver NK cells in PBC patients. Moreover, the cytotoxic activity and perforin expression by isolated NK cells were significantly increased in PBC patients associated with increased levels of plasma IL-8 and the expression of CD128a (IL-8 receptor) on NK cells. In contrast, the levels of IFN-γ, IL-6 and IL-8 synthesized by NK cells were significantly decreased in PBC patients as compared to controls. In conclusion, data from this study provide compelling evidence supporting a biologic role of NK cells in the immunopathogenesis of PBC.

Failure of HIV-exposed CD4+ T cells to activate dendritic cells is reversed by restoration of CD40/CD154 interactions

Because interactions between activated CD4+ T cells and antigen-presenting cells (APCs) are crucial for optimal APC function, defective CD4+ T-cell activation may contribute to APC dysregulation in HIV infection. Here, we show that CD4+ T cells exposed during stimulation to noninfectious HIV having functional envelope glycoproteins failed to provide activation signals to autologous dendritic cells (DCs). Consequently, important DC functions, including production of immunoregulatory cytokines (interleukin-12 p40 and interleukin-10) and up-regulation of costimulatory molecules (CD86, CD40, CD83), as well as the capacity to stimulate naive allogeneic T cells, were all adversely affected. The blunted up-regulation of CD154 in CD4+ T cells that were activated in the presence of noninfectious viruses is likely to be the major underlying mechanism for these defects. Addition of recombinant trimeric CD154 could restore production of cytokines by DCs cocultured with HIV-exposed T cells. Moreover, the functional defects mediated by coculture with HIV-exposed T cells were similar to those following antibody blockade of CD40-CD154 interactions. HIV-mediated blunted CD154 expression may thus play an important role in the suppression of cell-mediated immunity seen in HIV infection.

Immunoregulation in normal pregnancy and pre-eclampsia: an overview

Pre-eclampsia is a major disorder of human pregnancy, which may have an immunological basis. It is a disease of two stages. The first stage concerns the relative failure of early trophoblast invasion and remodelling of the spiral arteries, leading to a poor blood supply to the placenta, exposing it to oxidative stress. The inadequate trophoblast invasion may result from decreased expression of human leukocyte antigen-G (HLA-G) leading to an abnormal interaction with decidual natural killer (NK) cells, which are believed to play a major role in these processes through the production of immunoregulatory cytokines and angiogenic factors. Recent evidence suggests that the interaction between trophoblast human leukocyte antigen-C (HLA-C) olecules and decidual NK cell receptors may be the point at which the apparent partner specificity of the disease originates. The second stage is the maternal syndrome, which is characterized by a generalized systemic inflammatory response involving both leukocytes and endothelium. The inflammatory stimulus is believed to come from the placenta. In pre-eclampsia, placental oxidative stress may lead to increased shedding of apoptotic and/or necrotic syncytiotrophoblast debris into the maternal circulation. There is evidence that such trophoblast debris interacts with maternal leukocytes and endothelial cells to stimulate the release of proinflammatory cytokines, which could then trigger the maternal disease.

Vaccinia Virus Induces Strong Immunoregulatory Cytokine Production in Healthy Human Epidermal Keratinocytes: a Novel Strategy for Immune Evasion

Iatrogenic cutaneous infection with vaccinia virus (VV) and naturally occurring systemic infection with variola virus both lead to the characteristic skin "pox" lesions. Despite significant medical experience with both viruses, surprisingly little is understood about the interactions between these poxviruses and healthy resident skin cells. In recent years, it has become clear that skin plays an essential role in modulating both innate and adaptive immune responses, in part by producing and responding to a variety of cytokines and chemokines upon stimulation. Antagonists of many of these compounds are encoded in poxvirus genomes. Infection of skin cells with poxvirus may lead to a unique pattern of cytokine and chemokine production that might alter the cutaneous immune surveillance function. In this study, we infected primary cultures of human skin cells with VV and monitored antigen expression, virus replication, and cytokine production from the infected cells. While T cells, Langerhans cells, and dermal dendritic cells were infected abortively, keratinocytes, dermal fibroblasts, and dermal microvascular endothelial cells (HMVEC-d) all supported the complete virus life cycle. In contrast to the robust viral replication in fibroblasts and HMVEC-d, only limited viral replication was observed in keratinocytes. Importantly, VV infection of keratinocytes led to up-regulation of immunoregulatory and Th2 cytokines, including transforming growth factor beta, interleukin-10 (IL-10), and IL-13. We propose that the rapid induction of keratinocyte Th2 and immunoregulatory cytokines represents a poxvirus strategy to evade immune surveillance, and the limited viral multiplication in keratinocytes may be a protective mechanism to help the immune system "win the race."

Flt3 Ligand Treatment Reverses Endotoxin Tolerance-Related Immunoparalysis

Endotoxin tolerance, the secondary blunting of a subset of microbial product-driven responses, is presumed to provide protection from pathological hyperactivation of the innate immune system during infection. However, endotoxin tolerance can itself be harmful. A significant percentage of sepsis survivors exhibit the phenotype of systemic endotoxin tolerance, a state termed immunoparalysis. Similar immune hyporeactivity, associated with an elevated risk of succumbing to bacterial superinfection, is also seen in the aftermath of major trauma, surgery, and burns. We recently demonstrated that in vivo endotoxin tolerance in murine models involves dendritic cell loss as well as alterations in the responsiveness of macrophages and remaining dendritic cells. Furthermore, the kinetics of recovery from immunoparalysis-associated inhibition of proinflammatory and immunoregulatory cytokine production directly parallels the kinetics of dendritic cell repopulation in these models. Given this, we examined whether recovery from immunoparalysis could be accelerated therapeutically with flt3 ligand, a growth factor that stimulates the differentiation and mobilization of dendritic cells. Notably, administration of flt3 ligand rapidly reverses immunoparalysis in vivo, accelerating and amplifying repopulation of tissues with proinflammatory and immunoregulatory cytokine-producing dendritic cells.

Chronic Tick-Borne Encephalitis Virus Antigenemia: Possible Pathogenesis Pathways

Study of the proliferative potential and immunophenotype of lymphocytes and cytokine-producing capacity of mononuclear cells in patients with chronic tick-borne encephalitis virus antigenemia showed changes in T cell lymphoproliferative response, relative content of T cells and T helper inductors, immunoregulatory index, and imbalance in the production of immunoregulatory Th1 and Th2 cytokines.

C3 binding glycoprotein from Cuscuta europea induced different cytokine profiles from human PBMC compared to other plant and bacterial immunomodulators

The immunomodulatory properties of bioactive agents include the ability to induce cytokine production by the activated target cell. The effect of immunomodulatory C3 binding glycoprotein isolated from Cuscuta europea on the induction of human PBMC cytokine synthesis and the cell viability was investigated. Isolated PBMC from healthy donors were cultured for 24 h with C3bgp. We also studied the influence of C3bgp on the cytokine production in LPS, PHA, PWM and Dex treated PBMC. The quantitative determination of TNF-α, IL-12, IL-6 and IL-10 was performed in culture supernatant by ELISA. Results obtained demonstrated that C3bgp induced proinflammatory and immunoregulatory cytokine production, in the highest degree IL-12, followed by IL-6 and in lower degree TNF-α. IL-12 quantity was significantly increased in C3bgp stimulated cultures in comparison with LPS, PHA and PWM stimulated PBMC. C3bgp also increased IL-12 in PHA or PWM stimulated cultures, but not in LPS stimulated culture. C3bgp significantly increased IL-6 production compared to the PHA and PWM but not to LPS stimulation. On the other side, C3bgp inhibited IL-10 production after LPS, PHA and PWM stimulation. Cell viability in C3bgp stimulated cultures retained on the same level from 72 to 120 h of culturing, in contrast to LPS and PHA stimulated cultures. Based on the results presented, we conclude that the C3bgp exhibited immunomodulatory properties on the human PBMC. The ability of PDTC and Dex to down-regulate the effect of C3bgp on the proinflammatory cytokine production suggests that a part of the mechanism of action of C3bgp is mediated through NF-kB signal transduction pathway.

Reduced production of immunoregulatory cytokines in vitamin A- and zinc-deficient Indonesian infants

To determine effects of vitamin A, zinc and iron deficiency in Indonesian infants on the ability to produce immunoregulatory cytokines. Immunological assessment was done in 59 infants participating in a cross-sectional nutritional survey in rural West Java, Indonesia. Production of T-helper cell type-1 (Th1, cell-mediated) cytokines interferon-gamma (IFN-gamma), interleukin-12 (IL-12), interleukin-18 (IL-18) and T-helper cell type-2 (Th2, humoral) cytokine interleukin-6 (IL-6) were measured after stimulation with lipopolysaccharide and phytohemagglutinin in an ex vivo whole blood culture system. Circulating neopterin concentrations were determined as an indicator of in vivo macrophage activity. Of the infants, 48% were vitamin A deficient, 44% were anemic (with 17% having iron deficiency anemia), and 17% were zinc deficient. Vitamin-A deficient infants had significantly reduced ex vivo production of IFN-gamma, but also significantly higher circulating neopterin concentrations. Production of IFN-gamma and IL-12 were strongly correlated, IFN-gamma and IL-18 production were not. Zinc deficiency was accompanied by significantly reduced white blood cell counts and reduced ex vivo production of IL-6. Iron status was not related to cytokine production. This study shows that in vitamin A deficiency there is Th1 dominance in a steady state, combined however with impairment of the Th1 response after stimulation, whereas in zinc deficiency, there is a decreased Th2 response. Overall, vitamin A deficiency and zinc deficiency have marked albeit different effects on the immunocompetence of infants, affecting both cell-mediated and humoral components of the immune system.

Proinflammatory and anti-inflammatory cytokines in pregnant women chronically infected with Trypanosoma cruzi

Mother-to-child transmission of intracellular parasites could be related to the production of immunoregulatory cytokines. The levels of gamma interferon (IFN-γ), tumor necrosis factor-alpha (TNF-α) and lnterleukin (IL)-10 were evaluated during pregnancy in sera of women chronically infected with Trypanosoma cruzi that delivered infected or non-infected children. The levels of IL-10 increased in both, women only pregnant and only infected, compared to non-infected non-pregnant women. However, in pregnant women chronically infected with T. cruzi, IL-10 did not increase significantly, neither in the mothers of infected nor in the mothers of non-infected children. The levels of the inflammatory cytokine TNF-α were not affected in normal pregnancy but increased in the infected mothers of non-infected children. The levels of IFN-γ did not increase in the groups studied, indicating that the production of this pro-inflammatory cytokine was controlled, even when the levels of IL-10 did not increase, as in pregnant women chronically infected with T. cruzi.

Regulation of mite allergen-pulsed murine dendritic cells by respiratory syncytial virus.

Dendritic cells (DCs) are the only antigen-presenting cells that determine T-cell differentiation and play an important role in both allergy and viral infection. Respiratory syncytial virus (RSV) can infect DCs and affect their functions. The aim of this study was to determine the interaction between RSV infection and Dermatophagoides farinae allergen (D. farinae) sensitization on the development of allergy at the DC level. Murine bone marrow-derived DCs were prepared and treated as: control; D. farinae-pulsed DCs (D. farinae-DCs); ultraviolet-inactivated RSV challenged; RSV-infected, D. farinae-pulsed plus ultraviolet-inactivated RSV-challenged; and D. farinae-pulsed plus RSV-infected. In in vitro experiments, we compared the expression of costimulatory molecules and cytokine production between the six groups of DCs. Another group of naive mice were then intranasally inoculated with these DCs, after which intranasal challenge with D. farinae was performed to develop allergic airway inflammation in vivo. In comparison with D. farinae-DCs, D. farinae-pulsed plus RSV-infected DCs showed helper T cell (Th) 1-favored expression of costimulatory molecules and cytokine production. Allergic airway inflammation induced by intranasal instillation of D. farinae-DCs was abrogated when infected with RSV, which was associated with a concomitant suppression of Th2 response in the lung. Our results indicated that RSV suppresses D. farinae-DCs to induce Th2 response both in vitro and in vivo through regulation of expression of surface markers and production of immunoregulatory cytokines.

Intrathecal release of pro- and anti-inflammatory cytokines during stroke.

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of ischaemic brain damage. We have recently demonstrated that stroke patients display an intrathecal production of proinflammatory cytokines, such as IL-1beta and IL-6 already within the first 24 h after the beginning of symptoms (Tarkowski et al., 1995). The aim of the present study was to investigate patterns of local inflammatory responses as a consequence of acute stroke. Thirty stroke patients were studied prospectively on days 0-3, 7-9, 21-26 and after day 90 with clinical evaluations, radiological assessments and analysis of cerebrospinal fluid (CSF) cytokine levels. In addition, 15 healthy control CSF samples were used. Significantly increased CSF levels of IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-10 were observed early during the stroke with a peak on day 2 for the proinflammatory cytokines IL-8 and GM-CSF, and on day 3 for the immunoregulatory cytokine IL-10. Patients with a brain infarct predominantly located in the white matter showed significantly higher levels of IL-8 in CSF than patients with an infarct mainly located in the grey matter. Also, high levels of intrathecal tumour necrosis factor-alpha (TNF-alpha) were associated with the presence of white matter disease. Our study demonstrates an intrathecal production of proinflammatory and immunoregulatory cytokines in patients with stroke, supporting the notion of localized immune response to the acute brain lesion. A better understanding of the inflammatory response in stroke may lead to new treatment strategies.

Lower prevalence of IL-4 receptor α-chain gene 1902G variant in very-low-birth-weight infants with necrotizing enterocolitis

Background/purpose: Altered production of immunoregulatory cytokines is associated with the development of necrotizing enterocolitis (NEC) in preterm very low-birth-weight (VLBW) infants. According to data obtained in adults, functional genetic polymorphisms influence cytokine production capacity. The aim of this study was to evaluate whether functional polymorphisms of interleukin (IL)-1β, IL-4 receptor α-chain (IL-4ra), IL-6, and IL-10 genes might be associated with the risk of NEC in VLBW infants. Methods: Dried blood spot samples of 46 VLBW infants with NEC were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Samples from 90 VLBW infants without NEC were used as controls. Results: Infants with NEC carried the mutant variant of IL-4ra less frequently than controls (0.125 v 0.224; P < .05) even after adjustment for risk factors of NEC. No significant differences were found in the allelic frequencies of IL-1β, IL-6, and IL-10 genes between NEC and control infants. Conclusions: Carrier state of IL-4ra mutant allele might be associated with lower risk of NEC in VLBW infants. This genetic variant is associated with enhanced IL-4 effect. IL-4 is a major regulator of Th1-Th2 shift. The authors hypothesize that infants carrying the IL-4ra mutant allele might have Th2 skewness that might defend against the development of NEC.

Modulation of Kv channel expression and function by TCR and costimulatory signals during peripheral CD4(+) lymphocyte differentiation.

Ionic signaling pathways, including voltage-dependent potassium (Kv) channels, are instrumental in antigen-mediated responses of peripheral T cells. However, how Kv channels cooperate with other signaling pathways involved in T cell activation and differentiation is unknown. We report that multiple Kv channels are expressed by naive CD4+ lymphocytes, and that the current amplitude and kinetics are modulated by antigen receptor–mediated stimulation and costimulatory signals. Currents expressed in naive CD4+ lymphocytes are consistent with Kv1.1, Kv1.2, Kv1.3, and Kv1.6. Effector CD4+ cells generated by optimal TCR and costimulation exhibit only Kv1.3 current, but at approximately sixfold higher levels than naive cells. CD4+ lymphocytes anergized through partial stimulation exhibit similar Kv1.1, Kv1.2, and/or Kv1.6 currents, but approximately threefold more Kv1.3 current than naive cells. To determine if Kv channels contribute to the distinct functions of naive, effector, and anergized T cells, we tested their role in immunoregulatory cytokine production. Each Kv channel is required for maximal IL-2 production by naive CD4+ lymphocytes, whereas none appears to play a role in IL-2, IL-4, or IFN-γ production by effector cells. Interestingly, Kv channels in anergized lymphocytes actively suppress IL-4 production, and these functions are consistent with a role in regulating the membrane potential and calcium signaling.

Cell surface and cytokine phenotypes of skin immunocompetent cells involved in ultraviolet-induced immunosuppression

Immunocellular migrations out of and into the skin and modulations of functional cell surface molecules on antigen-presenting cells (APCs), as well as their immunoregulatory cytokine production, are important factors involved in the mechanism of UV-induced immunosuppression and tolerance. Of particular interest here are the effects of low-dose UVB exposures that can suppress the ability of a contact sensitizer to induce contact hypersensitivity (CHS) through the site (local immunosuppression) without inducing suppression of CHS induced through skin distant to the UV exposure. Such UV-irradiated skin has many changes with respect to composition of immunocompetent cells and cytokine production. After UV exposure, Langerhans cells/dendritic cells migrate from the skin to draining lymph nodes (DLNs) as they do from contact sensitizer-applied normal skin. On the other hand, UV causes monocytic/macrophagic cells to infiltrate into the dermis and then into the epidermis; these can also be shown to be induced by contact sesitizers to migrate to DLNs. Alterations in cell surface and immunoregulatory cytokine phenotypes of the cutaneous APCs in both the skin and DLNs are critical for CHS suppression and tolerance induction. Here we describe the phenotypic changes of immunocompetent cells in UV-irradiated skin in regard to CHS suppression and tolerance and methodologies to approach this area.

Production of interleukins 10 and 12 by activated peripheral blood monocytes/macrophages in patients suffering from chronic hepatitis C virus infection with respect to the response to interferon and ribavirin treatment

Circulating monocytes/macrophages are important for the initiation of immune responses to hepatitis C virus (HCV). Their presentation capacities and production of immunoregulatory cytokines enable them to activate cellular immune responses which is critical in determining the outcome of infection. We used flow cytometry to examine the expression of a CD80 costimulatory molecule on the surface of peripheral blood CD14+ monocytes/macrophages and to analyse the production of IL10 and IL12 by these cells. Forty-three individuals (6 asymptomatic HCV carriers, 37 patients with chronic hepatitis C (CHC)) were enrolled in this study. Thirty-seven patients with CHC (23 responders and 14 non-responders, NR) received combination (interferon+ribavirin) treatment for 52 weeks. The baseline percentage of CD14+CD80+ peripheral blood monocytes/macrophages was high in patients with CHC ( P<0.001) and returned to normal after the treatment. All patients with CHC showed significantly high production of IL10 ( P<0.001). In asymptomatic HCV carriers production level of this cytokine tended to be higher than in patients with CHC ( P<0.001). A baseline production of IL12 was higher in asymptomatic HCV carriers and patients with CHC compared to healthy controls ( P<0.001). The level of IL12 production was increased in treatment responders whereas in NR returned to normal value. Our data argue against functional impairment of circulating monocytes/macrophages during HCV infection. Furthermore, the positive therapeutic outcome following combination treatment might associate with increased production of IL12 by these cells.

Estrogen regulation of immune responses after injury

There is a naturally occurring gender difference in immune responses which persists after traumatic injury. Physiological levels of 17β-estradiol (E 2) are immunostimulatory, whereas high pregnancy and superphysiological levels are immunosuppressive. In contrast, at all concentrations, testosterone suppresses immune responses. Evidence from this laboratory and others suggest that the gender difference in immune responses after injury is mediated in part by alterations in the circulating levels of gonadal steroid hormones through modulation of production of inflammatory and immunoregulatory cytokines, including interleukin-6 (IL-6). Aberrant production of IL-6 is known to be an important mediator of immunity after injury. Since E 2 is a critical regulator of IL-6 production and overall immune function, it suggests gender specific therapies should be considered for the treatment of patients.