Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production

IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting IL-17 and IL-22. Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19- and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-γ and TNF-α. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.     

Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)‐6 produced during remission phase

T helper type 17 (Th17) cytokines have been implicated in the pathogenesis of neuromyelitis optica (NMO). As humanized anti‐interleukin (IL)‐6R (tocilizumab) immunoglobulin (Ig)G has been used as disease‐modifying therapy for NMO, the objective of our study was to investigate the role of endogenous IL‐6 on NMO‐derived CD4⁺ T cell behaviour. High production of IL‐6, IL‐17 and IL‐21 by CD4⁺ T‐cells was detected in NMO patients. Further, IL‐21 and IL‐6 levels were related directly to the level of neurological disabilities. The addition of anti‐IL‐6R IgG not only reduced directly the production of these cytokines, but also almost abolished the ability of activated autologous monocytes in enhancing IL‐6, IL‐17 and IL‐21 release by CD4⁺ T cells. In contrast, the production of IL‐10 was amplified in those cell cultures. Further, anti‐IL‐6R monoclonal antibodies (mAb) also potentiated the ability of glucocorticoid in reducing Th17 cytokines. Finally, the in‐vivo and in‐vitro IL‐6 levels were significantly higher among those patients who experienced clinical relapse during 2‐year follow‐up. In summary, our results suggest a deleterious role of IL‐6 in NMO by favouring, at least in part, the expansion of corticoid‐resistant Th17 cells.     

Association of cytokine Th2 gene polymorphisms with autoimmune thyroid diseases in Tunisian population

Autoimmune thyroid diseases (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are complex genetic diseases. Th2 cytokines act on the development of AITD. This study was conducted on Tunisian patients with AITD to investigate the association of Th2 cytokine gene polymorphisms and haplotype combination with GD or HT risk. A total of 156 controls, 160 patients with HT and 88 patients with GD were genotyped for IL‐4 rs2243250, IL‐5 rs2069812, IL‐6 rs1800796 and IL‐13 rs1800925 polymorphisms by PCR‐RFLP. The AITD risk was assessed by a logistic regression analysis using the SNP stats statistical program. False‐positive report probability (FPRP) was estimated to evaluate significant findings. IL‐13 rs1800925 was associated with GD, after adjustment for age and gender, in codominant, dominant and allele genetic models (p = .0072; p = .0018; p = .012, respectively). Significant association of the IL‐6 rs1800796C/G genotype with GD was also detected (p = .025). Furthermore, increased risk of HT was still found for IL‐13 rs1800925T allele (p = .039, OR = 1.39) and for IL‐4 rs2243250T/T genotype both in codominant (p = .033, OR = 2.59) and recessive (p = .011, OR = 2.73) models after adjustment for age and gender. Interestingly, haplotype analysis performed on the IL‐4, IL‐5 and IL‐13 genes revealed a high risk of HT with CTT haplotype (p = .008, OR = 2.12). However, the CCT haplotype is a protective factor (OR = 0.36). Patients carrying the CT haplotype with only one minor allele had a moderate risk of HT (OR = 1.56). The FPRP analysis showed that the association of IL‐13 rs1800925 polymorphism with GD and HT and the association of CTT haplotype with HT were noteworthy. In conclusion, the IL‐4, IL‐5, IL‐6 and IL‐13 polymorphism may play a role in susceptibility to GD and HT in the Tunisian population. Furthermore, gene–gene interaction between the IL‐4, IL‐5 and IL‐13 significantly increases the risk of AITD. Further studies with larger numbers of individuals are needed to confirm the results.     

Basophil modulation by cytokine instruction

Basophils have recently been recognized as critical effector cells in allergic reactions and protective immunity against helminths. Precise characterization of basophil biology could help to develop specific therapies that interfere with differentiation, tissue recruitment, or induction of effector functions and thereby ameliorate allergic disorders. The development, homeostasis, and effector functions of basophils are tightly regulated by extrinsic signals and in particular by cytokines. IL‐3, GM‐CSF, and thymic stromal lymphopoietin activate the STAT5 pathway that promotes proliferation, activation, and cytokine secretion but also induces a negative feedback loop via Pim‐1 and SOCS proteins. Basophils further express receptors for IL‐18 and IL‐33, which are associated with the signaling adaptor MyD88 and activate the NF‐κB and MAP kinase pathways. This review focuses on positive and negative regulation of basophils by these cytokines.     

Escherichia coli-induced expression of IL-1 alpha, IL-1 beta, IL-6 and IL-8 in normal human renal tubular epithelial cells

The aim of the present study was to investigate whether the IL-1 family cytokines, in addition to IL-6 and IL-8, could be induced in normal human cortical epithelial cells in response to bacterial stimuli. Human renal tissue was obtained from 9 patients undergoing elective tumour nephrectomy. Renal cortical epithelial cells of tubular origin were prepared from the unaffected tissue. The proximal tubular cells were stimulated for 2, 6 and 24 h with a heat-inactivated pyelonephritogenic Escherichia coli strain DS-17. Cultured unstimulated tubular cells served as controls. IL-1 alpha, IL-1 beta, IL-1 receptor antagonist, IL-6, IL-8, IL-10, TNF-alpha, G-CSF and GM-CSF were analysed using immunohistochemistry at the single cell level. The nonstimulated cells were found to express low levels of IL-6 and IL-8 (mean value < 3% of total cells). In contrast, E. coli exposure resulted in significantly increased incidences of IL-6 and IL-8 expressing cells (mean values approximately 18% of total cells) peaking within two hours of stimulation (P < 0.008 and P < 0.02 versus non-stimulated cells, respectively). A gradual decrease was thereafter observed at 6 and 24 h, respectively, although persistently higher compared to controls. A different kinetic response was found for IL-1 alpha, IL-1 beta and IL-1 receptor antagonist-expressing cells, which peaked 24 h after E. coli stimulation (mean values 3--10%) (P < 0.008, P < 0.02, P < 0.02 versus non-stimulated cells, respectively). Low levels of TNF-alpha and GM-CSF were found in 3 of the 9 donated epithelial cells, peaking at 2 h, and IL-10 and G-CSF producing cells in 1 patient each. In conclusion we found that heat-inactivated pyelonephritic E. coli induced a proinflammatory cytokine response in the normal human proximal tubular cells including the IL-1 family, IL-6 and IL-8.     

IL-23 up-regulates IL-10 and induces IL-17 synthesis by polyclonally activated naive T cells in human

Interleukin (IL)-23 is a heterodimeric cytokine of the IL-12 family. Human IL-23 is known to induce interferon (IFN)-gamma production and proliferation in T cells, preferentially in the CD45RO+ memory subset. Yet, its role in the differentiation of human naive T cells remains largely unknown. We investigated the effect of recombinant human (rh)IL-23 on cord blood CD4+ and CD8+ T cells during polyclonal activation. The IL-23 receptor complex was not detectable in resting naive T cells. Nevertheless, both IL-23 receptor subunits, IL-12Rbeta1 and IL-23R, were rapidly induced after activation in both naive CD4+ and CD8+ T cells. In both cell types, rhIL-23 enhanced IFN-gamma production. This effect was demonstrable as early as 2 days after activation, illustrating that a functional IL-23 receptor is rapidly induced in naive T cells upon activation. In naive CD8+ T cells, rhIL-23 specifically induced the secretion of IL-17, a pro-inflammatory cytokine. Moreover, rhIL-23 significantly increased the production of IL-10 in both naive CD4+ and CD8+ T cells. IL-17 and IL-10 levels were not affected by the addition of rhIL-12. We conclude that IL-23 induces a specific cytokine profile, remarkably distinct from IL-12, in activated human naive T cells.     

IL‐18, but not IL‐15, contributes to the IL‐12‐dependent induction of NK‐cell effector functions by Leishmania infantum in vivo

Activation of NK cells is a hallmark of infections with intracellular pathogens. We previously showed that the protozoan parasite Leishmania infantum triggered a rapid NK‐cell response in mice that required TLR9‐positive myeloid DC and IL‐12, but no IFN‐α/β. Here, we investigated whether IL‐15 or IL‐18 mediate the activity of IL‐12 or function as independent activators of NK cells. In contrast to earlier studies that described IL‐15 as crucial for NK‐cell priming in response to TLR ligands, the expression of IFN‐γ, FasL, perforin and granzyme B by NK cells in L. infantum‐infected mice was completely preserved in the absence of IL‐15, whereas the proliferative capacity of NK cells was lower than in WT mice. IFN‐γ secretion, cytotoxicity and FasL expression of NK cells from infected IL‐18^?/? mice were significantly reduced compared with controls, but, unlike IL‐12, IL‐18 was not essential for NK‐cell effector functions. Part of the NK‐cell‐stimulatory effect of IL‐12 was dependent on IL‐18. We conclude that IL‐15 is not functioning as a universal NK‐cell priming signal and that IL‐18 contributes to the NK‐cell response in visceral leishmaniasis. The cytokine requirements for NK‐cell activation appear to differ contingent upon the infectious pathogen.     

Distinct expression pattern of cytokines in semen of men with genital infection and oligo-terato-asthenozoospermia

PROBLEM: The objective of this study was to evaluate the possible relevance of cytokines in seminal plasma (SP) of patients with accessory gland infection and oligoterato-asthenozoospermia. METHOD OF STUDY: Semen samples were obtained by masturbation from 90 men and were examined for the presence of interleukin (IL)-2, IL-6, IL-8, IL-11 and soluble CD23 (sCD23) by enzyme-linked immunosorbent assay. Five groups were included: (1) fertile men (n = 20), (2) infertile men with varicocele and oligo-teratoasthenozoospermia (V-OTA, n = 20), (3) infertile men with genital infection and OTA (INF-OTA, n = 20), (4) infertile men with idiopathic testicular lesion and OTA (ITL-OTA, n = 20) and (5) infertile men with azoospermia (AZOO, n = 10). RESULTS: We found that the mean level of IL-2 was higher in SP from infertile men compared with SP from fertile men (P < 0.05). Mean levels of IL-6, IL-8, IL-11 in SP of INF-OTA were higher than that of all other groups (P < 0.05, P < 0.05, P < 0.001, respectively). However, no significant differences could be detected between other groups. A significant increase was noted in sCD23 levels in SP from men with ITL-OTA compared with all other groups (P < 0.01). We have not observed any correlations between IL-2, IL-6, IL-8, IL-11 and sCD23 levels in SP and semen parameters. Spearman's correlation coefficient revealed that there was a significant association between IL-6, IL-8, IL-11 levels in men with INF-OTA. CONCLUSION: The measurement of each cytokine separately in the SP of men with INF-OTA, in spite of the existing significant differences, does not have a diagnostic value in male infertility. However, a combined determination of IL-6, IL-8, IL-11 in the SP of men with genital infection and oligo-terato-asthenozoospermia may provide clinically useful information for the diagnosis of male accessory gland infection.     

Leukotrienes modulate cytokine release from dendritic cells

Leukotriene B(4) (LTB(4)) and cysteinyl leukotrienes (CysLTs) are known as potent mediators of inflammation, whereas their role in the regulation of adaptive immunity remains poorly characterized. Dendritic cells (DCs) are specialized antigen-presenting cells, uniquely capable to initiate primary immune responses. We have found that zymosan, but not lipopolysaccharide (LPS) stimulates murine bone marrow-derived dendritic cells (BM-DCs) to produce large amounts of CysLTs and LTB(4) from endogenous substrates. A selective inhibitor of leukotriene synthesis MK886 as well as an antagonist of the high affinity LTB(4) receptor (BLT(1)) U-75302 slightly inhibited zymosan-, but not LPS-stimulated interleukin (IL)-10 release from BM-DCs. In contrast, U-75302 increased zymosan-stimulated release of IL-12 p40 by approximately 23%. Pre-treatment with transforming growth factor-beta1 enhanced both stimulated leukotriene synthesis and the inhibitory effect of U-75302 and MK886 on IL-10 release from DCs. Consistent with the effects of leukotriene antagonists, exogenous LTB(4) enhanced LPS-stimulated IL-10 release by approximately 39% and inhibited IL-12 p40 release by approximately 22%. Both effects were mediated by the BLT(1) receptor. Ligands of the high affinity CysLTs receptor (CysLT(1)), MK-571 and LTD(4) had little or no effect on cytokine release. Agonists of the nuclear LTB(4) receptor peroxisome proliferator-activated receptor-alpha, 8(S)-hydroxyeicosatetraenoic acid and 5,8,11,14-eicosatetraynoic acid, inhibited release of both IL-12 p40 and IL-10. Our results indicate that both autocrine and paracrine leukotrienes may modulate cytokine release from DCs, in a manner that is consistent with previously reported T helper 2-polarizing effects of leukotrienes.     

Experimentally induced psoriatic lesion associates with interleukin (IL)-6 in mast cells and appearance of dermal cells expressing IL-33 and IL-6 receptor

Mast cells are involved in the development of psoriatic lesion, but it is not known how mast cells are activated or whether mast cell cytokines are expressed during the lesion development. In this study, the Köbner reaction was induced in uninvolved psoriatic skin of 18 patients using the tape‐stripping technique, and a sequence of biopsies was collected at 0 days, 2 h and 3 days or at 0 days, 1 day and 7 days for histochemical analysis. Eight patients developed the Köbner reaction verified at the follow‐up visit 2–2·5 weeks later. No significant differences were observed in total tryptase⁺ mast cells, psoriasis area and severity index and age/sex. Instead, the percentage of tryptase⁺ mast cells showing interleukin (IL)‐6 immunoreactivity was significantly higher in biopsies from Köbner‐positive patients than in those from Köbner‐negative patients. IL‐33 is a known inducer of IL‐6 in mast cells, and the number of IL‐33⁺ cells increased significantly in Köbner‐positive dermal skin at days 3–7. The number of dermal cells with IL‐6 receptor (IL‐6R, CD126) also increased in Köbner‐positive skin at days 3–7. Unexpectedly, the number of IL‐6R⁺ cells was even higher in Köbner‐negative skin at days 3–7. In the chronic plaque of 10 other psoriatic patients, the numbers of IL‐6⁺ mast cells and dermal cells showing IL‐6R were higher than those in the non‐lesional skin. In conclusion, the positive Köbner reaction is associated with IL‐6 in mast cells and appearance of IL‐6R⁺ and IL‐33⁺ dermal cells. This suggests that a previously unrecognized vicious circle may develop in the early psoriatic lesion.     

Type I cytokine profiles of human naïve and memory B lymphocytes: a potential for memory cells to impact polarization

B cells bifurcating along ‘type 1’ or ‘type 2’ pathways under the influence of polarizing cytokines can, in turn, influence the direction of an immune response. Here, we compare the capacity of human B cells residing within naïve and memory compartments to participate in type 1 polarizing responses. B‐cell receptor (BCR) engagement provided the main signal for interleukin (IL)‐12Rβ1 expression in the two subsets: this was potentiated by CD154 together with interferon‐γ (IFN‐γ) but inhibited by IL‐12. IL‐12Rβ2 could be induced on a minority of B cells by the same signals, and also by IFN‐γ alone. WSX‐1, a receptor for IL‐27, was expressed in both subsets with no evidence for its regulation by the signals studied. While neither subset was capable of secreting much IL‐12 p70, memory B cells could produce a small amount of IL‐12 p40 on CD40 ligation. Memory B cells also, exclusively, expressed IL‐23 p19 mRNA on BCR triggering. Importantly, products of appropriately stimulated memory – but not naive – B cells were shown to promote the synthesis of IFN‐γ in uncommitted T‐helper cells. The data indicate an equal capacity for naïve and memory B cells to respond within a type 1 polarizing environment. Although poorly equipped for initiating type 1 responses, B cells – by virtue of the memory subset – reveal a capacity for their maintenance and amplification following T‐dependent signalling.     

NK‐active cytokines IL‐2, IL‐12, and IL‐15 selectively modulate specific protein kinase C (PKC) isoforms in primary human NK cells

Natural killer (NK) cell function is largely modulated by growth factors and cytokines. In particular, interleukin (IL)‐2, IL‐12, and IL‐15 have major effects on the proliferative and cytotoxic activities of NK cells against tumor and virus‐infected cells. It is thought that the members of the protein kinase C (PKC) family of serine/threonine kinases play an important role in mediating the pleiotropic effects of cytokines on their target cells. We have investigated the downstream effects generated in purified human NK cells by IL‐2, IL‐12, and IL‐15 on PKCα and PKC?—a canonical and a novel isoform of PKC, respectively. By means of Western blotting, PKC activity assays, and immunofluorescence performed on highly purified preparations of primary human NK cells, we demonstrate that: 1) the three cytokines have similar effects on PKCα and PKC? activities; 2) whereas PKC? activity is induced by cytokine stimulation, PKCα activity is inhibited; and 3) both the induction of PKC? and the inhibition of PKCα functional activity are relatively early events in NK cells, while longer cytokine stimulations do not generate significant variations in enzyme activity, suggesting that the activation of both the canonical and novel isoforms of PKC are events required in the early phases of cytokine‐induced NK cell stimulation. Anat Rec 266:87–92, 2002. © 2002 Wiley‐Liss, Inc.     

IL-23-mediated regulation of IL-17 production in Helicobacter pylori-infected gastric mucosa

Helicobacter pylori (Hp) infection is associated with a marked infiltration of the gastric mucosa by inflammatory cells. The molecular pathways that control Hp-associated inflammatory reaction are complex, but locally induced cytokines seem to contribute to maintaining the ongoing inflammation. We have previously shown that IL-17 is over-produced in Hp-infected gastric mucosa, and that IL-17 stimulates the synthesis of IL-8, the major neutrophil chemoattractant. Factors/mechanisms that regulate IL-17 expression remain, however, unknown. In this study, we initially expanded our previous data, showing that CD4(+) and CD8(+) T cells are a source of IL-17 in Hp-infected samples. Since IL-23 enhances T cell-derived IL-17 during bacterial infections, we then assessed the role of IL-23 in controlling IL-17 expression in Hp-colonized stomach. Using real-time PCR and ELISA, IL-23 was detected in all gastric biopsies, but its expression was more pronounced in Hp-infected samples in comparison to controls. Treatment of normal gastric lamina propria mononuclear cells (LPMC) with IL-23 enhanced Stat3 activation and IL-17 secretion, and pharmacological inhibition of Stat3 prevented IL-23-driven IL-17 synthesis. Consistently, blockade of IL-23 in cultures of LPMC from Hp-infected patients reduced Stat3 activation and IL-17 production. Data show that IL-23 is overexpressed in Hp-infected gastric mucosa where it could contribute to sustaining IL-17 production.     

Membrane interleukin-18 revisits membrane IL-1α in T-helper type 1 responses

Although all structural studies on cytokine-cytokine receptor interactions are based on a crystallized cytokine binding to its specific receptor, there is no dearth of evidence that membrane-embedded cytokines are biologically active by virtue of cell-cell contact. Clearly the orientation of the membrane cytokine is such that it allows binding to the receptor, as takes place with the soluble form of the cytokine. In this issue, Bellora et al. [Eur. J. Immunol. 2012. 42: 1618-1626] report that interleukin-18 (IL-18) exists as an integral membrane protein on M-CSF-differentiated human macrophages and that upon LPS stimulation, IL-18 induces IFN-γ from NK cells in a caspase-1-dependent fashion. The immunological and inflammatory implications for this finding are considerable because of the role of IL-18 as the primary IFN-γ inducing cytokine in promoting Th1 responses.     

IL-15 in human visceral leishmaniasis caused by Leishmania infantum

Interleukin (IL)-15 is a recently discovered cytokine with the ability to stimulate the proliferation activity of Th1 and/or Th2 lymphocytes. Here, we investigated the involvement of IL-15 in the immune response to Leishmania infantum infection by studying patients with visceral leishmaniasis (VL). We found that IL-15 is produced by leishmanial antigen (LAg)-stimulated peripheral blood mononuclear cells (PBMC) from active VL patients at a significantly higher level than those produced by cells from healed VL subjects or healthy controls. A significant increase in IL-15 serum blood levels was also observed in acute VL patients compared with healed ones. Furthermore, recombinant IL-15 had an appreciable effect in vitro in reducing IL-4 and increasing the production of IL-12 in response to LAg, but it was ineffective in altering the production of interferon-gamma (IFN-gamma). The production of endogenous IL-15 in acute VL patients appeared to be insufficient to activate both IFN-gamma and IL-12, as attested by the absence of modification of these two cytokines by neutralization experiments in the presence of anti-IL-15 monoclonal antibodies (MoAB). On the contrary, the neutralization of IL-15 increased IL-4 production. Together, these results indicate that endogenous IL-15 plays a role in the suppression of Th2-type cytokines, even though it does not enhance the production of Th1 cytokines in acute VL patients. Since IL-15, in the presence of anti-IL-4 MoAb, caused a further increase in IL-12 production and led to a significant production of IFN-gamma, one of its indirect effects on Th1 cell activation could be due to the latter's effect on Th2 cytokines such as IL-4. Therefore, our observations indicate that there is a potential for IL-15 to augment the T-cell response to human intracellular pathogens.     

Reciprocal expression of IL‐25 and IL‐17A is important for allergic airways hyperreactivity

Background Interleukin (IL)‐25 (IL‐17E) is a potent inducer of the type‐2 immune effector response. Previously we have demonstrated that a neutralizing anti‐IL‐25 antibody, given during the establishment of ovalbumin‐specific lung allergy, abrogates airways hyperreactivity. Objective Blocking IL‐25 results in the suppression of IL‐13, a cytokine known to exacerbate pulmonary inflammation, and an unexpected reciprocal increase in IL‐17A. The role of IL‐17A in asthma is complex with reports of both pro‐inflammatory and anti‐inflammatory functions. Our aim was to determine the influence of IL‐17A in regulating IL‐25‐dependent lung allergy. Method Neutralizing antibodies to IL‐25 and/or IL‐17A were administered during an experimental model of allergic asthma. Bronchoalveolar cell infiltrates and lung cytokine production were determined to assess lung inflammation. Invasive plethysmography was undertaken to measure lung function. Results Neutralization of IL‐25 correlated with a decrease in IL‐13 levels and an increase in IL‐17A production, and an accompanying prevention of airway hyperresponsiveness (AHR). Notably, the blocking of IL‐17A reversed the protective effects of treating with anti‐IL‐25 antibodies, resulting in the re‐expression of several facets of the lung inflammatory response, including IL‐13 and eotaxin production, eosinophilia and AHR. Using mice over‐expressing IL‐13 we demonstrate that treatment of these mice with anti‐IL‐25 fails to suppress IL‐13 levels and in turn IL‐17A levels remain suppressed. Conclusions and Clinical Relevance IL‐13 is known to be an important inducer of lung inflammation, causing goblet cell hyperplasia and promoting airways hyperreactivity. Our data now demonstrate that IL‐13 also plays an important role in the genesis of lung inflammation downstream of IL‐25 by suppressing a protective IL‐17A response. These findings also highlight the important reciprocal interplay of the IL‐17 family members, IL‐25 and IL‐17A, in regulating allergic lung responses and suggest that the balance of IL‐17A, together with IL‐25, will be an important consideration in the treatment of allergic asthma. Cite this as: J. L. Barlow, R. J. Flynn, S. J. Ballantyne and A. N. J. McKenzie, Clinical & Experimental Allergy, 2011 (41) 1447–1455.     

IL-2 and IL-10 serum levels in HIV-1-infected patients with or without active antiretroviral therapy

We analyzed IL-2 and IL-10 serum levels in 26 HIV-1-infected patients naive of antiretroviral treatment and in 34 patients receiving highly active antiretroviral therapy (HAART). All patients without treatment were asymptomatic. When they were stratified according to levels of CD4+ T cells, IL-2 levels were significantly increased in patients with > or =200 CD4+/microl and IL-10 levels were significantly increased in patients with <200 CD4+/microl compared to controls. A significant negative correlation was observed between IL10 levels and CD4+ T-cell counts. No correlation was observed between IL-2 and IL-10 levels and viral load due to the wide range of variability in the number of HIV copies/ml present in the different patients. However, IL-2 levels were higher in patients with high viral load than in patients with low viral load. In patients with HAART, IL-2 and IL-10 levels were similar to the control group and no differences were detected respecting CD4+ T cells counts and viral load. Our findings show that the modifications in IL-2 and IL-10 serum levels in HIV-1-infected patients naive of antiretroviral treatment are associated with the progression of immunological damage. Furthermore, they show a dysbalance of type-1/type-2 cytokines with an involvement of type-2 cytokines in later stages of HIV infection. Cytokine dysregulation can be reversed by HAART in the context of immune restoration and viral suppression.