Effects of interferons on tumour necrosis factor alpha production from human keratinocytes

Interferons (IFNs) have been reported to have pleiotrophic effects including the ability to induce the production of other cytokines in several cell types. Tumour necrosis factor alpha (TNF-alpha) is pro-inflammatory cytokine a known to be produced by a variety of cells including human keratinocytes. In the present study, we sought to determine the effects of IFNs on TNF-alpha production from human keratinocytes. IFN-gamma (50-100 ng/ml) induced TNF-alpha production dose dependently, but no induction of TNF-alpha was observed with IFN-alpha or IFN-beta. Since in the epidermis cytokines often work with in a cascade fashion and keratinocytes are a source of primary cytokine, IL-1 alpha, whether combined treatment with IFN-gamma and IL-1 alpha had a synergistic effect on TNF-alpha production was examined. Combined treatment with IFN-gamma (100 ng/ml) and IL-1 alpha (10 ng/ml) induced 2-3-fold higher level of TNF-alpha than IL-1 alpha alone. These results suggest that IFN-gamma is a positive regulator for the production of TNF-alpha from human keratinocytes and likely to increase skin inflammation.     

Lack of correlation between the reduction of sevoflurane MAC and the cerebellar cyclic GMP concentrations in mice treated with 7-nitroindazole

The clinical spectrum of leishmaniasis and control of the infection are influenced by the parasite-host relationship. The role of cellular immune responses of the Th1 type in the protection against disease in experimental and human leishmaniasis is well established. In humans, production of IFN-gamma is associated with the control of infection in children infected by Leishmania chagasi. In visceral leishmaniasis, an impairment in IFN-gamma production and high IL-4 and IL-10 levels (Th2 cytokines) are observed in antigen-stimulated peripheral blood mononuclear cells (PBMC). Moreover, IL-12 restores IFN-gamma production and enhances the cytotoxic response. IL-10 is the cytokine involved in down-regulation of IFN-gamma production, since anti-IL-10 monoclonal antibody (mAb) restores in vitro IFN-gamma production and lymphoproliferative responses, and IL-10 abrogates the effect of IL-12. In cutaneous and mucosal leishmaniasis, high levels of IFN-gamma are found in L. amazonensis-stimulated PBMC. However, low or absent IFN-gamma levels were observed in antigen-stimulated PBMC from 50% of subjects with less than 60 days of disease (24 +/- 26 pg/ml). This response was restored by IL-12 (308 +/- 342 pg/ml) and anti-IL-10 mAb (380 +/- 245 pg/ml) (P < 0.05). Later during the disease, high levels of IFN-gamma and TNF-alpha are produced both in cutaneous and mucosal leishmaniasis. After treatment there is a decrease in TNF-alpha levels (366 +/- 224 pg/ml before treatment vs 142 +/- 107 pg/ml after treatment, P = 0.02). Although production of IFN-gamma and TNF-alpha might be involved in the control of parasite multiplication in the early phases of Leishmania infection, these cytokines might also be involved in the tissue damage seen in tegumentary leishmaniasis.     

Modulation of nitric oxide, hydrogen peroxide and cytokine production in a clonal macrophage model by the trichothecene vomitoxin (deoxynivalenol)

Characterization of how vomitoxin (VT) and other trichothecenes affect macrophage regulatory and effector function may contribute to improved understanding of mechanisms by which these mycotoxins impact the immune system. The RAW 264.7 murine cell line was used as a macrophage model to assess effects of the VT on proliferation and the production of nitric oxide (NO), hydrogen peroxide (H2O2) and cytokines. Using the MTT cleavage assay, VT at concentrations of 50 ng/ml or higher was found to significantly decrease proliferation and viability of RAW 264.7 cells without stimulation or with stimulation by lipopolysaccharide (LPS) or interferon (IFN)-gamma. In the absence of an activation agent, VT (25-250 ng/ml) had negligible effects on the production of NO, H2O2, and cytokines. Upon activation with LPS at concentrations of 10 to 100 ng/ml, VT at 25-100 ng/ml markedly enhanced production of H2O2 but was inhibitory at 250 ng/ml. VT enhancement of H2O2 production was observed as early as 12 h after LPS stimulation. When IFN-gamma was used as the stimulant, VT (25-250 ng/ml) delayed peak H2O2 production. VT (25-250 ng/ml) also markedly decreased NO production in cells activated with LPS or IFN-gamma. Interestingly, VT superinduced TNF-alpha and IL-6 production in LPS-stimulated cells and also elevated TNF-alpha in IFN-gamma stimulated cells. These results suggest that VT can selectively and concurrently upregulate or downregulate critical functions associated with activated macrophages.     

Novel delivery systems for coagulation proteins

Interferon-alpha (IFN-alpha) is an important molecule in the antiviral response, but cells from HIV-1-infected individuals show a reduced ability to secrete IFN-alpha. We investigated an association between an imbalance of type 1/type2 cytokines and the production of IFN-alpha in HIV-1 infection. We used whole blood culture to study the cytokine production profile, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), in response to HIV-1 antigens and to study the Sendai Virus and HSV-1-induced-production of IFN-alpha in seven HIV-1-infected patients. An impaired synthesis of IFN-alpha was obtained in patients with a predominant IL-4 production (IL-4 > IFN-gamma), and we found a positive correlation between the ex vivo production of IFN-alpha and the IFN-gamma/IL-4 ratio but not with the HIV RNA copy number in plasma. We investigated the role of T-cell-derived cytokines in the in vitro production of IFN-alpha by PBMC from eight healthy donors, activated with Sendai Virus or HSV-1. Whereas type 2 cytokines (IL-4, IL-13) inhibited virus-induced IFN-alpha synthesis, on the contrary, type 1 cytokines (IL-2, IFN-gamma) enhanced it. A disarray in the T-cell-derived cytokine response may play a role in the defect of IFN-alpha production in HIV-1-infected individuals. Further investigations are needed to explore this hypothesis.     

Generation of nitric oxide and induction of major histocompatibility complex class II antigen in macrophages from mice lacking the interferon gamma receptor

Availability of mice with a targeted disruption of the interferon gamma (IFN-gamma) receptor gene (IFN-gamma R0/0 mice) made it possible to examine parameters of macrophage activation in the absence of a functional IFN-gamma receptor. We asked to what extent other cytokines could replace IFN-gamma in the induction of nitric oxide or major histocompatibility complex class II antigen (Ia) expression in peritoneal macrophages. In thioglycollate-elicited macrophages from wild-type mice, tumor necrosis factor (TNF) alone was virtually ineffective in inducing release of NO2- (the endproduct of nitric oxide generation), but TNF enhanced NO2- release in the presence of IFN-gamma. In macrophages from IFN-gamma R0/0 mice, which were unresponsive to IFN-gamma, TNF completely failed to stimulate NO2- release. The stimulatory actions of IFN-alpha/beta on NO2- release were indistinguishable in wild-type and IFN-gamma R0/0 macrophages: IFN-alpha/beta was ineffective on its own, showed marginal stimulation of NO2- release in combination with TNF, and was moderately effective in the presence of lipopolysaccharide. The level of constitutive Ia antigen expression was not significantly different in peritoneal macrophages from wild-type and IFN-gamma R0/0 mice. An increased Ia expression was induced by IL-4 and granulocyte-macrophage colony-stimulating factor in both wild-type and IFN-gamma R0/0 macrophages, but the magnitude of this induction was less than with optimal concentrations of IFN-gamma in macrophages from wild-type mice. IFN-alpha/beta showed only a minor stimulatory effect on Ia expression in both wild-type and IFN-gamma R0/0 macrophages. Simultaneous treatment of wild-type macrophages with IFN-alpha/beta and IFN-gamma reduced the IFN-gamma-induced Ia expression in wild-type macrophages, but IFN-alpha/beta did not show an inhibitory effect on IL-4- or granulocyte-macrophage-colony-stimulating factor-induced Ia expression in either wild-type or IFN-gamma R0/0 macrophages. The important role of IFN-gamma in the regulation of the induced expression of major histocompatibility complex class II antigen was confirmed by showing that after systemic infection with the BCG strain of Mycobacterium bovis resident peritoneal macrophages from IFN-gamma R0/0 mice had a lower level of Ia expression than macrophages from wild-type mice. The inability of other cytokines to substitute fully for IFN-gamma in macrophage activation helps to explain the earlier observed decreased resistance of IFN-gamma R0/0 mice to some infections.     

Effects of interferon-gamma, interleukin-1 beta, and tumor necrosis factor-alpha on the serotonin metabolism in the nucleus raphe dorsalis of the rat

The effects of the cytokines interferon (IFN)-gamma, interleukin (IL)-1, and tumor necrosis factor (TNF)-alpha on the serotoninergic transmission in the nucleus raphe dorsalis (NRD) were studied after peripheral and central application. The studies were performed in the freely moving rat using differential pulse voltammetry with multicarbon fibre electrodes to study the extracellular levels of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA). The extracellular 5-HIAA levels were not changed in the NRD after peripheral application of rat recombinant IFN-gamma, but elevated by the cytokines IL-1 beta and TNF-alpha. After intracerebroventricular (i.c.v.) application the cytokines IFN-gamma, IL-1 beta and TNF-alpha stimulated the serotoninergic transmission in the NRD. Our data suggest that the effect of peripherally elevated cytokine concentrations on the serotonin metabolism in the NRD of the rat is cytokine-dependent. In this respect the T-cell and NK-cell cytokine IFN-gamma acts clearly different when compared to the mainly macrophage-derived cytokines IL-1 beta and TNF-alpha, and plays a different role in the communication between immune and central nervous system.     

Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is caused by the hyperactivation of T cells and macrophages. The clinical characteristics associated with this disease result from overproduction of Th1 cytokines including interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-alpha). In this study, we analyzed the production of IL-12 and IL-4, which determine Th1 and Th2 response, respectively, and IL-10, which antagonizes Th1 cytokines, in 11 patients with HLH. IL-12 was detected in plasma in all patients (mean peak value, 30.0 +/- 5.0 pg/mL), while IFN-gamma was massively produced in nine patients (mean peak value, 79.2 +/- 112.0 U/mL). IL-4 was not detected in any of the patients. Plasma IL-10 levels were elevated in all patients (mean peak value, 2,698.0 +/- 3,535.0 pg/mL). There was a positive correlation between the levels of IFN-gamma and IL-10 (P < .01). The plasma concentrations of these cytokines were initially high, before decreasing after the acute phase. However, the decrease in IL-10 levels was slower than that of IFN-gamma. Although the concentration of IL-12 was high at the acute phase, in some patients, a peak in the level was delayed until the chronic phase. Thus, in HLH, production of cytokines that promote development of Th1 cells appears to be predominant over that for Th2 cell development. Overproduction of IL-10 was also observed indicating that a mechanism suppressing hyperactivation of Th1 cells and monocytes/macrophages functions in patients with this disease.     

Kinetics of intraocular cytokines in the suppression of experimental autoimmune uveoretinitis by type I IFN

The systemic administration of IFN-alpha/beta was previously found to suppress inflammation in rats with experimental autoimmune uveoretinitis (EAU); however, an effect on the systemic immune response was not identified. In order to investigate an immunological basis for suppression at the intraocular level, rats immunized with interphotoreceptor retinoid-binding protein (IRBP) were administered daily intramuscular injections of 10(5) IU IFN-alpha/beta and cytokines were measured by ELISA in intraocular extracts prepared by ultrasonification at various timepoints throughout the course of EAU. In control EAU, intraocular concentrations of IFN-gamma were found to be non-detectable on day 8 before the onset of inflammation, significantly elevated on day 12 at peak inflammation (182+/-106 pg/ml), then non-detectable again on day 16 after inflammation had begun to subside. In contrast, intraocular IFN-gamma in IFN-alpha/beta-treated rats remained non-detectable or low at all timepoints. Measurement of intraocular IL-2 revealed no difference between the two groups of rats. Intraocular IL-4 concentrations were elevated in rats treated with IFN-alpha/beta, although this cytokine was also detected in the same range in controls as well as normal rats. Finally, intraocular IL-10 was non-detectable on day 8, significantly elevated at peak inflammation on day 12 (588+/-139 pg/ml), then decreased to low levels on day 16 in control EAU rats, while remaining non-detectable or low in IFN-alpha/beta-treated rats. These results suggest that acute inflammation in IRBP-induced EAU in rats involves both IFN-gamma and IL-10 at the local intraocular level, and that systemic administration of IFN-alpha/beta inhibits EAU via a mechanism that involves suppression of both cytokines.     

Role of liver NK cells and peritoneal macrophages in gamma interferon and interleukin-10 production in experimental bacterial peritonitis in mice

Gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-10 (IL-10) production by liver, spleen, lung, peripheral blood mononuclear cells (MNC), and peritoneal exudate cells (PEC) in experimental bacterial peritonitis was examined by cecum ligation and puncture (CLP) (with an 18-gauge needle) of BALB/c mice. MNC of organs were cultured for 18 h, and cytokine levels in supernatants were examined. Cytokines contained in peritoneal lavage fluid were regarded as those produced by PEC. Only liver MNC and PEC produced substantial amounts of IFN-gamma, and PEC were the main source of IL-10, especially 12 h after CLP. As reflected by the cytokine production by liver MNC and PEC, serum IFN-gamma and IL-10 levels were elevated after CLP. C57BL/6 (B6) mice and BALB/c nude mice showed a similar pattern of cytokine production. TNF-alpha levels in culture supernatants, peritoneal lavage fluid, and sera were not significantly elevated compared to those of sham-operated mice. In vivo depletion of NK cells of B6 mice with anti-asialo GM1 or anti-NK1.1 antibody greatly decreased IFN-gamma levels in liver MNC culture supernatants and sera, suggesting that liver NK cells are IFN-gamma producers. On the other hand, plastic-adherent PEC macrophages are the major IL-10 producers. Mice subjected to a cecum ligation and cut procedure (which have a more severe peritonitis) showed much higher IFN-gamma and IL-10 levels than those subjected to CLP, while mice subjected to CLP with a smaller (22-gauge) needle showed low levels of these cytokines. These findings show that liver NK cells and PEC macrophages are important for the production of proinflammatory and anti-inflammatory cytokines in bacterial peritonitis.     

Alterations in tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 production by natural killer cell-enriched peripheral blood mononuclear cells in chronic alcoholism: relationship with liver disease and ethanol intake

No previous studies have been reported on human alcoholism in which the pattern of cytokine secretion by natural killer (NK) cells is explored. The goal of the present study was to evaluate the role of NK cells in the production of cytokines in patients with chronic alcoholism, analyzing at the same time the possible relationship between cytokine production and both alcoholic liver disease and ethanol (EtOH) intake. A total of 30 chronic alcoholic patients-11 without liver disease [alcoholics without liver disease (AWLD) group] and 19 diagnosed of alcoholic liver cirrhosis-were included in this study. Twenty-five age- and sex-matched healthy volunteers were analyzed as controls. Production of interferon (IFN)-gamma, tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6 was performed on NK-enriched peripheral blood mononuclear cells (PBMC) after stimulation with IL-2 and IFN-alpha. In AWLD patients, the production of TNF-alpha was significantly reduced, compared with normal controls, under both IFN-alpha (p < 0.01) and IL-2 (p < 0.05) stimulation. In patients with cirrhosis, TNF-alpha production by PBMC enriched in NK cells varied depending on the EtOH intake status at the moment of evaluation. Accordingly, an increased concentration of this cytokine was detected in the supernatants of cirrhotic patients and active EtOH intake, particularly after IFN-alpha stimulation (p < 0.05); whereas, in patients with at least 1 year of alcohol withdrawal, TNF-alpha levels remained within normal range. The results on the production of IL-6 and IFN-gamma in AWLD and cirrhotic patients showed that only cirrhotic patients with a prolonged EtOH withdrawal period display abnormal production. Accordingly, in this group of patients, a significantly increased release of IL-6 was observed after both IFN-alpha and IL-2 stimulation (p < 0.01 and p < 0.05, respectively). By contrast, a lower IFN-gamma production (p < 0.005) was detected with respect to the control group. Our results point to the existence of an abnormal cytokine secretion by NK cells from chronic alcoholism patients, which depend on both the existence of liver disease and the status of EtOH intake.     

Quinolinic acid production is related to macrophage tropic isolates of HIV-1

We sought to determine whether the neurotoxin quinolinic acid (QUIN) was produced by macrophages or lymphocytes infected with isolates of HIV-1 with varying degrees of macrophage tropism derived from patients with varying stages of AIDS dementia complex (ADC). Highly macrophage tropic isolates and minimally macrophage tropic isolates were used to inoculate macrophages and QUIN production was measured. Similarly, QUIN production from macrophages was monitored using a purified cell free highly macrophage tropic isolate and laboratory isolates SF33 and SF2. Each of these experiments was also performed with lymphocytes. We found that macrophages infected with macrophage tropic isolates of HIV-1 led to QUIN production while lymphocytes did not produce QUIN. The ability of the HIV-1 infected macrophages to produce QUIN was related to the viral inoculum and the degree of macrophage tropism of the isolate. The severity of ADC in the patient from whom a particular isolate was derived was not per se a determining factor for QUIN production. Purified cell free ADC isolates also led to QUIN production by macrophages thereby suggesting that HIV-1 infection alone is capable of inducing QUIN production.     

Interleukin-18 enhances lipopolysaccharide-induced interferon-gamma production in human whole blood cultures

Interleukin-18 (IL-18) is a newly described cytokine, formerly called interferon-gamma (IFN-gamma)-inducing factor. In a simple 24-h human whole blood culture, IFN-gamma was produced by the combination of lipopolysaccharide (LPS) plus IL-18. To liberate cytokines in the leukocyte and red cell compartments, the detergent Triton X-100 was added to the entire blood culture. The combination of low concentrations of LPS plus IL-18 induced a 3- to 5-fold greater production of IFN-gamma than did either stimulant alone. Tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8 were also produced. The presence of IL-10 completely suppressed the production of IFN-gamma and reduced that of TNF-alpha, IL-6, and IL-8. Thus, IFN-gamma, TNF-alpha, IL-8, and IL-6 are produced in a single whole blood culture, making correlations in the synthesis of a T helper type 1 cytokine and proinflammatory cytokines with disease activity possible in a single culture.     

Features of the cytokines secreted by adult T cell leukemia (ATL) cells

Adult T cell leukemia (ATL) cells show a mature helper-inducer T cell phenotype and are thought to secrete many kinds of cytokines in vivo, complicating the clinical features in these patients. In an attempt to specify the cytokines produced by ATL cells, we measured the cytokine concentration in the culture supernatants of three ATL cell lines, all of which were confirmed to be true peripheral blood ATL cell in origin. All these cell lines showed the same cytokine production profile, secreting IL1-alpha, IL1-beta, LD78(MIP-l alpha), TNF-alpha, IFN-gamma, and GM-CSF, but not secreting IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1 Ra), IL-4, IFN-alpha, and G-CSF irrespective of the stimulatory agents used. Such limited cytokine production may indicate the specific origin of ATL cells within the helper-inducer T cell subtypes. Moreover, these results explain some of the unusual clinical features of ATL patients.     

Decision tree in hematologic diseases: for a rationalization of histologic, phenotypic and genotypic diagnosis

The regulatory role of soluble cytokines in innate cellular immune responses induced by Pneumocystis carinii was assessed in vitro in direct comparison to induction by Listeria monocytogenes. This report shows that P. carinii organisms, as well as L. monocytogenes, stimulated in whole spleen cell cultures of SCID mice the release of IFN-gamma, TNF-alpha/beta, IL-10, IL-12, and iNO. This response was independent of functional T cells. Both macrophages (M phi) and natural killer (NK) cells were necessary for either microorganism to induce release of these cytokines. Cocultures of purified M phi--including alveolar M phi--and purified NK cells indicated that no other cell population was necessarily involved. Microbial induction of NK cell-derived IFN-gamma has been reported to be mediated by the combined effects of TNF-alpha and IL-12 released by M phi upon adequate microbial stimulation. Interestingly, only L. monocytogenes, but not P. carinii organisms could directly induce detectable amounts of TNF-alpha/beta, IL-12, or iNO in purified M phi cultures. In dose-response experiments, release of IFN-gamma, TNF-alpha/beta, and iNO was reduced at high relative concentrations of either microorganism. This high-dose suppression was at least partially controlled by M phi-produced IL-10. Our data show that, P. carinii potently induces activating and inhibitory innate cellular immune response mechanisms and indicate that the initial step of macrophage-mediated NK cell activation might also involve other pathways than those described to date.     

Effects of ginkgolides on interleukin-1, tumor necrosis factor-alpha and nitric oxide production by rat microglia stimulated with lipopolysaccharides in vitro

The effects of ginkgolide A (CAS 15291-75-5, BN52020, GA) and B (CAS 15291-77-7, BN52021, GB) on interleukin (IL)-1, tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production in resting and lipopolysaccharide (LPS)-stimulated neonatal rat microglia were studied. Apafant (CAS 105219-56-5), a platelet activating factor (PAF) antagonist of triazolobenzodiazepine type was used as control. The biological activities of IL-1 and TNF-alpha were tested by mouse thymocyte proliferation and L929 cytotoxicity assay, respectively. NO concentration was represented by nitrite and determined by Griess reaction. GA 1 nmol/1-10 mumol/l inhibited IL-1 production, and 100 nmol/l-10 mumol/l decreased TNF-alpha and NO production in dose-dependent manner. GB inhibited IL-1, TNF-alpha and NO production at the concentrations 10 nmol/l-10 mumol/l, 100 nmol/l-10 mumol/l and 10 nmol/l-10 mumol/l, respectively. Apafant inhibited IL-1, but not TNF-alpha and NO production. GB plus apafant (50 mumol/l) showed IL-1 and NO inhibitory effects, but not on TNF-alpha. The manner was different from that of GB or apafant alone. The results suggested that GA and GB inhibited proinflammatory cytokines and NO production from LPS-stimulated rat microglia, however, apafant inhibited IL-1 production only. The effects of GA and GB on proinflammatory cytokines and NO production from rat microglia do not seem to be based on PAF receptor antagonism. In addition, GA and GB are regarded as promising agents for the treatment of some neurodegenerative diseases in the central nervous system.     

Acid sphingomyelinase-derived ceramide is not required for inflammatory cytokine signalling in murine macrophages

Sphingomyelin hydrolysis is induced in myeloid cell-lines by tumour necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1beta), and interferon gamma (IFN-gamma). Ceramide, a product of sphingomyelin hydrolysis, recapitulates many of the cellular responses elicited by these cytokines, and this has lead to the hypothesis that ceramide is a second messenger of cytokine signalling. Sphingomyelin hydrolysis is catalysed by an acid spingomyelinase (ASMase) and one or more neutral sphingomyelinases (NSMase); both ASMase and NSMase are activated during cytokine signalling. In the present study, the contribution of ASMase to TNF-alpha, IL-1beta, and IFN-gamma signalling in murine macrophages was addressed. Cytokine-induced responses were compared in macrophages derived from the bone marrow of AMSase null and wild-type mice. Specifically, TNF-alpha-and IFN-gamma-induced nitric oxide production and TNF-alpha- and IL-1beta-induced expression of the alpha-chemokine, KC, were intact in ASMase null macrophages. Furthermore, TNF-alpha induction of p42/p44 ERK and p38-MAPK phosphorylation, c-jun kinase activation, and IkappaBalpha degradation were normal. Also normal in ASMase null macrophages was TNF-alpha-, IL-1beta- and IFN-gamma-induced expression of a panel of early response genes. It is concluded that ASMase is non-essential for the inflammatory signals activated in murine macrophages by TNF-alpha, IL-1beta and IFN-gamma.     

Severe aplastic anaemia relapsing during a pregnancy; spontaneous remission following termination

IFN-gamma and TNF-alpha plasma levels were measured before and after local treatment in 27 patients. Twenty healthy subjects served as controls. Plasma concentrations of IFN-gamma and TNF-alpha were significantly higher before treatment (178.7 +/- 11.9 pg/ml and 31.9 +/- 11.6 pg/ml, respectively) compared to the control group (139.6 +/- 7.86 pg/ml and 17.1 +/- 7.7 pg/ml, respectively). After treatment IFN-gamma levels were significantly decreased (151.3 +/- 8.3 pg/ml) toward the control group values and TNF-alpha levels were observed even lower than in the controls (11.48 +/- 6.8 pg/ml). No correlations were found between age, duration of psoriasis and plasma levels of cytokines. However, IFN-gamma levels were related, although not significantly, to disease severity (evidenced by the PASI score). The data support the important proinflammatory role of IFN-gamma and TNF-alpha in the clinical manifestation of psoriasis.