Ozone-induced alterations in collagen metabolism of rat lungs

Rats were exposed to amounts of ozone ranging from 0.5 to 2.0 ppm for intervals of 1, 2, or 3 weeks. Collagen synthesis rates in their lungs were quantitated by biochemical analyses performed with lung minces. Correlative histological observations were made in different lung lobes from the same rats. At all levels of ozone tested, collagen synthesis rates of the lungs were significantly elevated and histologically discernible fibrosis of the alveolar duct walls was observed. Within the range of ozone concentrations studied, the elevation of collagen synthesis rate in exposed rats was a linear function of the level of ozone to which the animals were exposed. We conclude that exposure of rats to near-ambient levels of ozone causes biochemically and histologically discernible fibrotic changes in their lungs, suggesting that such effects may occur at levels of ozone at or near the current ambient air quality standard for this pollutant.     

Ozone-induced alterations in collagen metabolism of monkey lungs: Use of biopsy-obtained lung tissue

Open-chest biopsies of lung were performed on three cynomolgus monkeys (Macaca fascicularis) 4–6 weeks before and immediately after exposure to 1.5 ppm of ozone for 1 week. Two control monkeys were subjected to comparable procedures, but were exposed to filtered air for 1 week immediately prior to the second biopsy. Collagen synthesis rate of each lung biopsy specimen was determined. Enhanced rates of collagen synthesis were observed in the lung biopsy specimens obtained from the monkeys exposed to ozone; elevated rates of collagen synthesis were not observed in lung biopsy specimens from the two monkeys undergoing identical surgical procedures but not exposed to ozone. We conclude that exposures of monkeys to high levels of ozone caused increased rates of collagen synthesis in their lungs, suggesting that the ozone-induced fibrotic changes observed previously in rat lungs also occur in lungs anatomically similar to those of humans. This experimental design, in which each animal serves as its own control, is a practical way to perform such exposure experiments using small numbers of valuable animals.     

Effect of sub-chronic endosulfan exposure on humoral and cell-mediated immune responses in albino rats

The present study was designed to evaluate the effect of sub-chronic doses of endosulfan on humoral and cell-mediated immune (CMI) responses in albino rats. Male albino rats were given a diet containing 5, 10 or 20 ppm endosulfan for 8–22 weeks and immunized with tetanus toxoid in Freund's complete adjuvant subcutaneously 20 days before terminating the exposure. The humoral immune response was studied by serum globulin level, immunoglobulin (IgM and IgG) concentration and antibody titre against tetanus toxoid. The CMI response was studied by leucocyte migration inhibition (LMI) and macrophage migration inhibition (MMI) factors. The antigen-induced increases in serum globulin fraction and immunoglobulin level were reduced at high doses of the endosulfan after 12 weeks of exposure. Antibody titre was significantly decreased in endosulfan-exposed rats at 10 and 20 ppm levels and a consistent trend was observed. Rats in the 10 and 20 ppm dose groups had significantly depressed LMI and MMI responses. Results obtained in this study revealed marked suppression of the humoral and CMI responses in rats administered with sub-chronic doses of endosulfan. Both cellular and humoral immune responses were decreased in a dose-time dependent pattern. Suppression of immune responses by endosulfan is clearly an important aspect of its toxicology.     

Inhibitory effect of saponin fraction from Codonopsis lanceolata on immune cell-mediated inflammatory responses

Saponin components are known to be pharmaceutically, cosmetically and nutraceutically valuable principles found in various herbal medicine. In this study, we evaluated the inhibitory role of saponin fraction (SF), prepared from C. lanceolata, an ethnopharmacologically famous plant, on various inflammatory responses managed by monocytes, macrophages, lymphocytes and mast cells. SF clearly suppressed the release of nitric oxide (NO) and tumor necrosis factor (TNF)-α, but not prostaglandin E₂ (PGE₂). While this fraction did not scavenge the reactivity of SNP-induced radicals in RAW264. 7 cells, it negatively modulated the phagocytic uptake of macrophages treated with FITC-dextran. Interestingly, SF completely diminished cell-cell adhesion events induced by both CD29 and CD43, but not cell-fibronectin adhesion. Concanavalin (Con) A [as well phytohemaglutinin A (PHA)]-induced proliferation of splenic lymphocytes as well as interferon (IFN)-γ production were also clearly suppressed by SF treatment. Finally, SF also significantly blocked the degranulation process of mast cell line RBL-2H3 cell as assessed by DNP-BSA-induced β-hexosaminidase activity. The anti-inflammatory activities of SF on NO production seemed to be due to inhibition of nuclear factor (NF)-κB activation signaling, since it blocked the phosphorylation of inhibitor of κB (IκB)α as well as inducible NO synthase (iNOS) expression. Therefore, these results suggest that SF may be considered as a promising herbal medicine with potent anti-inflammatory actions.     

Suppression of humoral and cell-mediated immune responses in vitro by benzo(a)pyrene

The effect of benzo(a)pyrene (BaP) at different molar (M) concentrations on the in vitro anti-sheep red blood cell (SRBC) plaque (antibody) forming cell (PFC) response and the one-way mixed lymphocyte response (MLR) was tested. Inhibition of the PFC response and the MLR occurred when spleen cells were exposed to a wide range of BaP concentrations from 10(-4) M to 10(-8) M. Maximum depression of the responses occurred at 10(-5) M for PFC production (47% of controls) and for the MLR (19% of controls) as measured by a stimulation index. No significant loss in cell viability was observed at this or lower molar concentrations of BaP. The non-carcinogenic analog of BaP, benzo(e)pyrene, did not suppress PFC responses at comparable concentrations. This in vitro system will facilitate manipulations of T and B lymphocytes and macrophages (adherent cells) in a controlled culture environment for precisely characterizing the sensitivity of these cells and their subpopulations on exposure to BaP.     

Modulation by the insecticides heptachlor and chlordane of the cell-mediated immune proliferative responses of rhesus monkeys.

Peripheral blood mononuclear cells (PBMC) were isolated from heparinized blood samples from twelve young, healthy male rhesus monkeys. Triplicate cultures were made in RPMI 1640 with 10% heat-inactivated homologous plasma with or without the test mitogens (phytohemagglutinin, concanavalin A and pokeweed mitogen). Under a defined assay condition, although a different monkey responded to a different degree (3 to 4-fold difference in stimulation index) to a specific mitogen, the proliferative responses of all monkeys were affected significantly by the addition of the chlorinated hydrocarbon heptachlor or chlordane to the test cultures. The insecticides, at 10-40 microM, may also act as mitogens for the unstimulated monkey PBMC or stimulate the release of IL-2 from a mitogen-stimulated culture. At 80 microM, both heptachlor and chlordane completely suppressed the proliferation and IL-2 release of the monkey lymphocytes. These studies suggest immunomodulatory effects of the insecticides heptachlor and chlordane.     

The influence of opioids on the humoral and cell-mediated immune responses in mice. The role of macrophages

BackgroundOur experiments were aimed to test the influence of treatment with different opioids (morphine, fentanyl, methadone) on the humoral and cell-mediated immune responses.MethodsMice were treated intraperitoneally (ip) with opioids for several days and next either immunized with sheep red blood cells (SRBC) to test the antibody production or skin-sensitized with hapten picryl chloride (PCL) to induce contact hypersensitivity (CHS). In addition, the effects of opioids on the production of reactive oxygen intermediates (ROIs) and cytokines by peritoneal macrophages (Mf) and on the expression of surface markers on these cells and blood leukocytes were estimated.ResultsOpioids caused an enhancement of ROIs and cytokines production when macrophages were stimulated with zymosan or lipopolysaccharide (LPS) and reduced the expression of antigen presentation markers on Mf. Numbers of anti-SRBC plaque forming cells (PFC) and antibodies titres were lower in mice treated with all tested opioids. Depending on the use of particular opioid and the phase of allergic reaction, effects of the treatment on CHS were diverse. While morphine decreased the early and late phases of induction of CHS responses, methadone increased both reactions. In case of the effector phase of CHS, morphine and fentanyl increased both its early and late stages, while methadone decreased the late reaction. Treatment of recipients with opioids had diverse influence on the passive transfer of CHS in these animals.ConclusionsOur experiments show that the action of opioids on the immune system is a complex phenomenon dependent on such variables as type of opioid, character of response (humoral versus cellular) and types of cells involved. Here Mf seem to play a significant role.     

Potency of cell-mediated immune responses to different combined HIV-1 immunogens in a humanized murine model

In this study, cell-mediated immune responses were evaluated in HLA-A2.1 mice that received polycistronic vector expressing HIV-1 gp120, gag and pol or single vectors expressing gp120 + gag/pol as well as recombinant structural proteins and adjuvants. Mice primed with the polycistronic DNA/CpG and boosted with the same regimen plus proteins induced a higher T-cell proliferative response to gp120. However, a very high frequency of IFN-gamma was detected in mice receiving the mixture of gp120 + gag/pol DNA constructs, recombinant proteins and CpG. We also measured specific CD8+T cells in PBMCs by intracellular cytokine and HLA-A2.1-peptide dimer staining in response to HLA-A2.1-restricted HIV-1 epitopes (gp120, gag and pol). The group that received single gp120 + gag/pol DNA constructs, recombinant proteins and CpG had a higher CD8+T cell response to the combination of peptides compared to the other groups that received the polycistronic construct. The present study reveals an optimal combination of immunogens to enhance immune responses against HIV-1.     

Glycidol modulation of the immune responses in female B6C3F1 mice

The immunotoxic potential of glycidol was evaluated in female B6C3F1 mice using a battery of functional assays and three host resistance models. Glycidol was administered to the animals by oral gavage as a solution in sterile distilled water daily for 14 days at doses of 25, 125 and 250 mg/kg. In tier I, we observed that glycidol exposure produced a dose-related decrease in splenocyte IgM antibody-forming cell response to sheep red blood cells (sRBC); the spleen natural killer (NK) cell activity was also decreased. A decrease in B cell proliferative responses to anti-IgM F(ab')2 and/or interleukin-4 (IL-4) was observed while the splenocyte proliferative responses to T cell mitogen ConA and B cell mitogen LPS were not affected. The splenocyte proliferative response to allogeneic cells as evaluated in the mixed leukocyte reaction (MLR) to DBA/2 spleen cells was not affected. In tier II, we found that exposure to glycidol decreased the number and percentage of B cells and the absolute number of CD4+ T cells in the spleen while the number of total T cells, CD8+ T cells and CD4+CD8+ T cells was not affected. The cytotoxic T lymphocyte (CTL) response to mitomycin C-treated P815 mastocytoma was not affected; the cytotoxic activity of peritoneal macrophages was not suppressed. Moreover, the host resistance to Listeria monocytogenes was not affected although a slight increase in host resistance to Streptococcus pneumoniae was observed. However, exposure to glycidol decreased host resistance to the B16F10 melanoma tumor model with the maximal tumor formation in lung observed in the high dose group. Overall, these dada support the finding that glycidol is an immunosuppressive agent in female B6C3F1 mice.     

Effects of social manipulations and environmental enrichment on behavior and cell-mediated immune responses in rhesus macaques

This paper reviews a series of studies that have examined the effects of manipulations to the social and the inanimate environments on the behavior and cell-mediated immune responses of rhesus macaques of various ages living in different settings. In general, enrichment of the inanimate environment with toys, structures, foraging devices, and/or videotapes increased the amount of species-typical behavior expressed by the monkeys, but did not affect their immune responses. Housing monkeys socially, on the other hand, not only resulted in increased time spent in species-typical activities, but also resulted in (1) decreases in time spent in abnormal behavior and (2) changes in a number of immune parameters. Additionally, attempts to directly influence the affiliative interactions of socially housed adult rhesus have resulted in systematic changes in affiliative behavior, although anticipated accompanying systematic alterations to cell-mediated immune responses have yet to be realized. The data suggest that aspects of the physical and social environments influence behavioral and immunological parameters in captive macaques in the absence of other experimental manipulations. As such, these influences need to be appropriately managed and/or controlled in order to minimize potential confounds in experimental designs.     

Effects of isolated compounds from Catalpa ovata on the T cell-mediated immune responses and proliferation of leukemic cells

Three compounds were isolated from the ethyl acetate soluble fraction of the methanolic extract of the leaves of Catalpa ovata (Bignoniaceae) through repeated column chromatography. We investigated the effects of these compounds on T cell-mediated responses for tumor surveillance and proliferation in U937, HL60, and Molt-4 leukemia cells. Compounds 1–3 inhibited proliferation of those cells in a dose-dependent manner. Compound 3 showed mild effect in Molt-4 cell cytotoxicity. Compound 3 enhanced gene expressions of p53 and IL-4, but decreased IL-2 and IFN-Γ genes in Molt-4 cell. Our findings indicate that compound 3 may enhance T cell-mediated immune responses and anticancer properties.     

Humoral and cell-mediated immune responses elicited by poly (dl-lactide) adjuvanted filarial antigen molecules

Abstract

Context: In our recent studies, Brugia malayi molecules have shown interesting immune-stimulating and immune-suppressive properties. Among these, F6 a pro-inflammatory (54–68 kDa) SDS-PAGE resolved fraction of the parasite when administered with Freund’s complete/incomplete adjuvant in animals, elicited both Th1 and Th2 type immune responses and protects the host from filarial parasite.

Objective: The present study was aimed at developing biodegradable microspheres for filarial antigenic protein molecules and to investigate the immunoadjuvanticity of microspheres (Ms)-loaded F6 molecules.

Materials and methods: Poly-lactide microspheres (DL-PLA-Ms) were prepared using double emulsification and solvent evaporation method; and studied their size, shape, antigen adsorption efficiency, in-process stability, and antigen release profiles. F6 and B. malayi adult worm (BmA: ～17 to 180 kDa) protein molecules adsorbed on the Ms were administered in a single shot into Swiss mice, subcutaneously, and investigated their immunoadjuvant effect and compared with one/two doses-schedule of plain F6/BmA.

Results: Immunization with F6/BmA-loaded DL-PLA-Ms resulted in upregulation of cellular proliferation, IFN- γ, TNF-α and NO release from host’s cells stimulated with F6/BmA or LPS/Con A, IgG, IgG1 and IgG2a levels. These responses were well comparable with the responses produced by two doses of plain BmA/F6.

Discussion and conclusion: In conclusion, a single dose of DL-PLA-Ms-F6 induced predominantly Th1 immune responses and well comparable with two doses of plain F6. This is the first ever report on potential of DL-PLA-Ms as adjuvant for filarial immunogen.     

Comparison of humoral and cell-mediated immune responses to cationic PLGA microspheres containing recombinant hepatitis B antigen

Presently available marketed alum adsorbed hepatitis B vaccine used for prophylactic immunization, can effectively elicit humoral immunity but is poor inducer of cell-mediated immunity (CMI). Besides, conventional alum-adjuvant vaccines require multiple injections to achieve long-lasting protective immune responses. Therefore, as a result of insufficient immunization, infections are still the leading killer among diseases. The present investigation was therefore, aimed at developing "single-shot" HBsAg adsorbed microspheres of poly (DL)-lactide-co-glycolide (PLGA) (L/G 50:50 and 75:25) and their capability to stimulate the cell mediated immune response against hepatitis B surface antigen. These microspheres were characterized in vitro for their size, shape polydispersity index, percentage HBsAg adsorption efficiency and in vitro release profile. The immune-stimulating activities were also studied following subcutaneous injection of HBsAg adsorbed PLGA microspheres (single-dose on day 0) and compared with alum adsorbed vaccines (two-doses on 0 and 28 days) in Balb/c mice. Specific cell-mediated immune responses such as lymphocyte transformation assay (stimulation-index) including release of interferon-gamma (IFN-γ), interleukin-2 (IL-2) and nitric-oxide were determined. Cellular responses in case of alum adsorb HBsAg vaccine was very low. These studies demonstrate the potential of cationic polymeric microspheres based vaccine in stimulating cell mediated immune response along with humoral response against hepatitis B.     

Eugenol modulation of the immune response in mice

The effect of eugenol on selected parameters of the immune response of C57BL/6 mice was studied. In a dose-response study, eugenol at high doses completely inhibited the plaque-forming cell responses of splenocytes to the T-dependent antigen (sheep erythrocytes) both in vitro and in vivo. In vitro, at concentrations higher than 1.0 mM, eugenol was found to be cytotoxic. In vivo, however, at very low doses there appeared to be a suppression of the plaque-forming cell response to sheep erythrocytes, reaching maximal suppression at 0.1 mumol eugenol/kg mouse body weight. This was followed by enhancement of the response, peaking at 0.25 mumol eugenol/kg mouse body weight. These changes correlated fairly well with body weight changes. Thymic weights appeared to remain unchanged for all doses except the 1.0 mumol eugenol/kg body weight, which was significantly (p less than 0.05) higher than the rest of the groups. Natural killer activity at all effector:target ratios (100:1, 50:1, 25:1) was significantly (p less than 0.05) enhanced at both 0.25 and 2.5 mumol eugenol/kg body weight. Overall, eugenol seems to have dose-dependent suppressive and enhancing effects on the immune response. These effects represent an atypical multiphasic response in which an inversed dose-response relationship is observed.     

Manipulating the immune system: humoral versus cell-mediated immunity

Many of the vaccines in use today were designed on an empirical basis with little understanding of the mechanism of protective immunity or knowledge of the protective antigens. Certain of these vaccines, based on killed or attenuated bacteria or viruses, are associated with unacceptable side-effects. New generation vaccines based on recombinant proteins or naked DNA have considerably improved safety profiles, but are often poorly immunogenic, especially when administered by mucosal routes. This is a particular problem with oral delivery; where high doses of antigen are required to generate even modest immune responses. In contrast, nasal delivery of antigens with a range of adjuvants or delivery systems has been shown to generate relatively potent immune responses and to protect against infection in animal models. Advances in immunology have demonstrated that a variety of cellular and humoral immune effector mechanisms, that are regulated by distinct Th1 and Th2 subtypes of T cells, mediate protection against different infectious diseases. The identification of adjuvants and immunomodulators, that can promote the selective induction of these distinct populations of T cells, has now made it possible to rationally design safe and effective mucosal vaccines against a range of infectious diseases of man.     

Immunodepressive activity of FCE 23762 on humoral and cell-mediated immune responses in normal mice: comparison with doxorubicin.

FCE 23762 (3' desamino-3'[2(s)methoxyl-4-morpholinyl]doxorubicin) is a new doxorubicin (Dx) derivative that has been selected for clinical testing for its favourable antitumor characteristics, which include efficacy on Dx-resistant tumors. Immunosuppression is an undesirable side-effect of anti-cancer chemotherapy and the therapeutic efficacy of Dx is probably also related to its low immunotoxicity. It was, thus, of interest to compare the effects of FCE 23762 and its parental drug on the immune responses. Both compounds were injected i.v. into healthy mice at equitoxic doses and according to different treatment schedules. Single doses of FCE 23762 and Dx, given concomitant or after the antigen, suppressed at the same degree and dose-dependently the primary anti-SRBC antibody response. Following a multiple treatment schedule after the antigen, FCE 23762 was less suppressive than Dx on both primary and secondary antibody production. Differently from Dx, that was completely inactive, FCE 23762 moderately inhibited DTH reaction to SRBC, only at the highest single dose tested or for repeated administrations given simultaneously or after priming. Both drugs were totally ineffective in delaying skin allograft rejection. Since spleen cellularity and ex vivo lymphocyte proliferation to Con A and LPS were similarly impaired by the two drugs, the differentiated immunodepressive activity of FCE 23762 and Dx cannot be merely associated to their cytotoxic and antiproliferative action. The hypothesis of a selective effect on different regulatory cell subsets and/or immune mechanisms is discussed.     

Effect of L-arginine on restraint stress induced modulation of immune responses in rats and mice.

The present study investigates the role of nitric oxide (NO) on restraint stress (RS)-induced modulation of humoral and cell-mediated immune responses in rats and mice. RS produced suppression of humoral immune response, i.e., anti-SRBC antibody titre ( 7.38 +/- 0.32 versus 4.13 +/- 0.30; mean +/- S.E.M., P < 0.001). In case of cell-mediated immunity, in delayed type hypersensitivity (DTH) response the change in paw volume decreased from 0.069 +/- 0.003 mm (mean +/- S.E.M.) in control non-stressed group to 0.038 +/- 0.002 mm in the stressed group (P < 0.001) while percentage leucocyte migration inhibition (% LMI) decreased from 39.7 +/- 1.95 in control non-stressed animals to 15.2 +/- 1.07 in animals subjected to stress (P < 0.01). Pretreating the animals with an NO precursor, L-arginine (1000 mg kg-1, i.p.) antagonized the effect of RS on humoral (anti-SRBC antibody titre 6.50 +/- 0.27 versus 4.13 +/- 0.30, P < 0.001 ) and cell-mediated (DTH response 0.066 +/- 0.002 mm versus 0.038 +/- 0.002 mm, P < 0.001; % LMI 41.5 +/- 1.46 versus 15.2 +/- 1.07, P < 0.01) immune responses. Administration of 7-nitroindazole (7-NI, 50 mg kg-1, i.p.), an inhibitor of neuronal NO synthase, alone further enhanced the immunosuppressive effect of RS (anti-SRBC antibody titre 2.75 +/- 0.25 versus 4.13 +/- 0.30, P < 0.001; DTH response 0.019 +/- 0.002 mm versus 0.038 +/- 0.002 mm, P < 0.001; % LMI 5.0 +/- 1.08 versus 15.2 +/- 1.07, P < 0.01). However, when given before L-arginine treatment, 7-NI reversed the effect of the latter drug on stress-induced immunomodulation (anti-SRBC antibody titre 3.00 +/- 0.27 versus 6.5 +/- 0.27, P < 0.001; DTH response 0.043 +/- 0.003 mm versus 0.066 +/- 0.002 mm, P < 0.001; % LMI 12.0 +/- 0.93 versus 41.5 +/- 1.46, P < 0.01). Unlike its effect on RS-induced immune responsiveness, L-arginine (250, 500, 1000 mg kg-1) when given for 5-7 days to naive non-stressed animals produced dose dependent suppression of both humoral (anti-SRBC antibody titre 6.4 +/- 0.32 versus 5.4 +/- 0.32, 4.0 +/- 0.27, 3.1 +/- 0.30, respectively) and cell-mediated (DTH 0.065 +/- 0.003 mm versus 0.064 +/- 0.004 mm, 0.039 +/- 0.003 mm, 0.020 +/- 0.002 mm, respectively and % LMI 37.52 +/- 1.58 versus 30.48 +/- 1.07, 28.18 +/- 1.22, 19.76 +/- 0.83, respectively) immune responses. 7-NI significantly blocked these immunosuppressive effects of L-arginine (anti-SRBC antibody titre 6.0 +/- 0.38 versus 3.1 +/- 0.030, P < 0.01; DTH response 0.056 +/- 0.004 mm versus 0.020 +/- 0.002 mm, P < 0.001; % LMI 34.76 +/- 1.31 versus 19.76 +/- 0.83, P < 0.01). However, 7-NI when given to non-stressed animals failed to modulate immune responsiveness. Thus, NO appears to play an important role in RS-induced immunomodulation and these effects are different from its effect on immune responsiveness in non-stressed animals.     

Effect of Thuja occidentalis and its polysaccharide on cell-mediated immune responses and cytokine levels of metastatic tumor-bearing animals

Context: Tumor microenvironment induces an active immune tolerance and escapes immune surveillance. In order to achieve an effective antitumor immune response, appropriately activated immune cells should maintain their antitumor activity to overcome the immune suppressive tumor microenvironment.

Objectives: This study focuses on the effect of Thuja occidentalis L. (Cupressaceae) extract and its polysaccharide (TPS) on cell-mediated immune response (CMI) in metastasis bearing mice.

Materials and methods: Metastasis was induced by injecting B16F-10 melanoma cells in mice through the tail vein and effector mechanisms of CMI was studied by analyzing cytotoxic T-lymphocyte (CTL) activity, natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent complement-mediated cytotoxicity (ACC). The effect of T. occidentalis and TPS on pro-inflammatory cytokines and tissue inhibitor matrix metalloproteinases (TIMP) levels were also analyzed.

Results and discussion: Administration of T. occidentalis and TPS enhanced the NK cell activity, ADCC and ACC much earlier than the control tumor-bearing animals. T. occidentalis and TPS were also found to decrease the elevated level of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, GM-CSF and tumor necrosis factor (TNF)-α in the serum of metastatic tumor-bearing animals. The level of antitumor factors such as IL-2 and TIMP was elevated by the treatment with T. occidentalis and TPS in the serum, which was lowered in the untreated tumor-bearing animals.

Conclusion: This study clearly suggests that T. occidentalis and TPS effectively stimulate cell-mediated immune system and decrease pro-inflammatory cytokines, thereby inhibiting metastasis of tumor cells.