Neopterin-induced expression of intercellular adhesion molecule-1 (ICAM-1) in type II-like alveolar epithelial cells

In order to examine the regulatory effects of major Th1-derived cytokines, such as IL-12, and Th2 cytokines, IL-4 and IL-10, on the formation of neopterin and degradation of tryptophan, two metabolic pathways induced by interferon-gamma (IFN-gamma) in human monocytes/macrophages, we investigated the human monocytic cell line THP-1, primary human macrophages, and peripheral blood mononuclear cells (PBMC). Neopterin formation and tryptophan degradation were induced similarly by IFN-gamma in all three cell types investigated, but the effects of interleukins were different between THP-1, primary macrophages and PBMC. In PBMC, but not in THP-1 cells and primary macrophages, IL-12 was found to be additive to the effects of IFN-gamma to superinduce neopterin formation and tryptophan degradation. IL-4 and IL-10 reduced the effects of IFN-gamma on monocytic cells, and both cytokines were additively antagonistic to IFN-gamma in PBMC and THP-1 cells. Finally, on preincubation, but not on addition of IL-12, the effects of IL-4 and IL-10 on PBMC could be abrogated, whereas no such effect was seen in THP-1 cells. The results show that IL-12 up-regulates neopterin formation and tryptophan degradation by inducing additional IFN-gamma production by Th1 cells, while a direct effect of IL-12 on monocytes/macrophages appears to be absent. Similarly, IL-4 and IL-10 inhibit neopterin production and tryptophan degradation in PBMC by down-regulating Th1-type cytokine production and possibly also via direct deactivation of IFN-gamma effects towards monocytes/macrophages. The results clearly show how Th1 cell-mediated immunity may be up- or down-regulated by endogenous cytokine production.     

Neopterin release from human endothelial cells is triggered by interferon-gamma.

Human umbilical vein endothelial cells (HUVEC) were investigated for their ability to produce neopterin, a biochemical marker for an activated immune system. Interferon-gamma (IFN-gamma), IL-1 alpha, IL-2, IL-6, tumour necrosis factor-alpha, granulocyte/macrophage colony stimulating factor, phytohaemagglutinin and concanavalin A were used to stimulate HUVEC. While IFN-gamma induced neopterin release from HUVEC in a time- and dose-dependent manner, all the other cytokines used had no effect on neopterin production. High neopterin levels are found in patients with rejection episodes or infections. Our results suggest that not only monocytes and macrophages, which are known to synthesize neopterin, but also endothelial cells are responsible for these high serum neopterin levels.     

Nickel-induced IL-10 down-regulates Th1- but not Th2-type cytokine responses to the contact allergen nickel

Whereas the involvement of Th1- and Th2-type cytokines in contact allergy to nickel (Ni) is well documented, the role of the regulatory cytokine IL-10 is less clear. We therefore investigated the impact of IL-10 on Ni-induced Th1- (IFN-gamma) and Th2-type (IL-4 and IL-13) cytokine responses in human peripheral blood mononuclear cells (PBMC). PBMC from 15 blood donors with reactivity to Ni (Ni-PBMC) and 8 control donors devoid of reactivity (control PBMC) were stimulated with Ni and the frequency of cytokine-producing cells and the levels of secreted cytokines were analysed by ELISpot (IL-4, IL-13 and IFN-gamma) and ELISA (IL-10, IL-13 and IFN-gamma), respectively. The Ni-induced response was further assessed in the presence of recombinant IL-10 (rIL-10) or neutralizing antibody to IL-10 and the phenotype of the Ni-specific cytokine-producing cells regulated by IL-10 was determined by cell depletion experiments. Ni induced IL-10 production in Ni-PBMC (mean, (range); 33.1 pg/ml (0-93.4 pg/ml)) but not control PBMC (2.2 pg/ml (0-14.9 pg/ml)) (P = 0.002). Ni also induced significant production of IL-4, IL-13 and IFN-gamma that correlated with the IL-10 response. Addition of rIL-10 down-regulated the Ni-induced production of all cytokines but with a more pronounced effect on IFN-gamma. However, neutralization of Ni-induced IL-10 enhanced the levels of IFN-gamma induced by Ni (P = 0.004) but did not affect the number of IFN-gamma-producing cells or the production of other cytokines. Cell depletion experiments suggested that the Ni-specific IFN-gamma (and Th2-type cytokine) producing cells were CD4(+) T cells. The impact of IL-10 on Ni-induced IFN-gamma responses by CD4(+) T cells suggests that an important role of IL-10 in vivo is to counteract the allergic reactions mediated by Th1-type cytokines.     

Interaction of Mycobacterium tuberculosis-Induced Transforming Growth Factor β1 and Interleukin-10

Mycobacterium tuberculosis is associated with the activation of cytokine circuits both at sites of active tuberculosis in vivo and in cultures of mononuclear cells stimulated by M. tuberculosis or its components in vitro. Interactive stimulatory and/or inhibitory pathways are established between cytokines, which may result in potentiation or attenuation of the effects of each molecule on T-cell responses. Here we examined the interaction of transforming growth factor beta1 (TGF-beta1) and interleukin-10 (IL-10) in purified protein derivative (PPD)-stimulated human mononuclear cell cultures in vitro. TGF-beta1 induced monocyte IL-10 (but not tumor necrosis factor alpha) production (by 70-fold, P < 0.02) and mRNA expression in the absence but not in the presence of PPD. Both exogenous recombinant (r) IL-10 and rTGF-beta1 independently suppressed the production of PPD-induced gamma interferon (IFN-gamma) in mononuclear cells from PPD skin test-positive individuals. Synergistic suppression of IFN-gamma in cultures containing both rTGF-beta1 and rIL-10 was only seen when the responder cell population were peripheral blood mononuclear cells (PBMC) and not monocyte-depleted mononuclear cells and when PBMC were pretreated with rTGF-beta1 but not with rIL-10. Suppression of PPD-induced IFN-gamma in PBMC containing both rTGF-beta1 (1 ng/ml) and rIL-10 (100 pg/ml) was 1.5-fold higher (P < 0.05) than cultures containing TGF-beta1 alone and 5.7-fold higher (P < 0.004) than cultures containing IL-10 alone. Also, neutralization of endogenous TGF-beta1 and IL-10 together enhanced PPD-induced IFN-gamma in PBMC in a synergistic manner. Thus, TGF-beta1 and IL-10 together potentiate the downmodulatory effect on M. tuberculosis-induced T-cell production of IFN-gamma, and TGF-beta1 alone enhances IL-10 production. At sites of active M. tuberculosis infection, these interactions may be conducive to the suppression of mononuclear cell functions.     

Regulation of cytokine production in human peripheral blood mononuclear cells and allergen-specific th cell clones by 1alpha,25-dihydroxyvitamin D3

BACKGROUND: The steroid hormone 1alpha,25-dihydroxyvitamin D3 (calcitriol), in addition to its crucial role in calcium homeostasis, exerts several effects on the immune system by regulating cell proliferation, differentiation, and maturation. These effects may be exerted through the control of protooncogenes and the regulation of cytokine production. METHODS: The influence of calcitriol on cytokines secretion by human peripheral blood mononuclear cells (PBMC) isolated from healthy donors, and by allergen-specific T helper (Th) cell clones was studied. PBMC were cultured for 48 h with phorbol myristate acetate (PMA) and ionomycin in the presence or absence of calcitriol. Human Th cell clones were stimulated with either Bet v 1 allergen or anti-CD3 antibodies and PMA. Cytokines were measured in the supernatants by ELISA, and at single-cell level by FACS. RESULTS: Calcitriol significantly inhibited the production of IL-2, IFN-gamma and IL-12 by PBMC, as well as the percentage of CD4+ T cells containing intracytoplasmic IL-2 and IFN-gamma. Interestingly, calcitriol-treated PBMC induced the production of IL-10 and IL-5, but not of IL-4. The effect of calcitriol was maximal at 10(-7) to 10(-9) and noneffective at 10(-11) M. Calcitriol diminished the secretion of IL-1, TNF-alpha, and MG-CSF in PBMC. Furthermore, calcitriol also decreased the secretion of IL-2 and IFN-gamma by Th1 clones, and of IL-4 by Th2 clones. CONCLUSIONS: Our data strongly support the notion that calcitriol modulates the production of cytokines in a time- and concentration-dependent manner, and suggest that nonhypercalcemic derivatives of 1alpha,25-dihydroxyvitamin D(3) may be used for new immunosuppressive therapies.     

Monocyte-derived dendritic cells release neopterin

Increased neopterin concentrations in body fluids are found in diseases associated with activated, cell-mediated immunity including infections, autoimmune diseases, and certain malignancies. Monocytes/macrophages are known to secrete large amounts of neopterin upon stimulation with interferon-gamma (IFN-gamma). Ontogenetically, the major part of dendritic cells (DC) belongs to the myeloid lineage. Therefore, we investigated whether cultured monocyte-derived DC can elaborate neopterin. Cells were treated with cytokines in the presence or absence of monocyte-conditioned medium as a maturation stimulus. DC secreted an average 3.5 nmol/l neopterin. In response to IFN-gamma, cells significantly increased their output of neopterin. In distinction to monocytes/macrophages, neopterin production in DC was highly sensitive to IFN-alpha and IFN-beta. Further, lipopolysaccharides (LPS) enhanced neopterin synthesis, whereas tumor necrosis factor alpha, interleukin (IL)-1beta, IL-2, IL-10, and IL-18 were ineffective. Simultaneously, tryptophan degradation by induction of indoleamine (2,3)-dioxygenase (IDO) was tested in stimulated cells. Our results showed that IFN-gamma as well as LPS are inducers of IDO in DC.     

Cytokine regulation of human monocyte interleukin-1 (IL-1) production in vitro. Enhancement of IL-1 production by interferon (IFN) gamma, tumour necrosis factor-alpha, IL-2 and IL-1, and inhibition by IFN-alpha.

IL-1 production (secreted and cell-associated) was measured in monocyte cultures stimulated by a variety of agents in vitro. Monocytes either adherent to conventional plastic culture plates in serum-free conditions, or in suspension in culture medium containing serum were stimulated to produce IL-1 during culture. In non-adherent, serum-free conditions, monocytes produced very low or undetectable amounts of IL-1 during 20 h of culture. Lipopolysaccharide (LPS) induced equivalent amounts of secreted and cell-associated IL-1, although at very low concentrations more cell-associated IL-1 was produced. IL-1 production in response to LPS could be augmented by crude lymphokine, IFN-gamma, or tumour necrosis factor (TNF) alpha. TNF-alpha preferentially augmented the production of cell-associated IL-1 in LPS-stimulated cultures. TNF-alpha induced a significant amount of IL-1 (mainly cell-associated) directly but could also induce IL-1 secretion when combined with IL-2 or IFN-gamma, or when in the presence of serum. IL-2 acted synergistically with low concentrations of IFN-gamma or IL-1 to induce significant levels of IL-1 production. IFN-alpha did not induce any IL-1 production, but was a potent inhibitor of IL-1 production induced by a variety of stimuli. These results suggest that IL-1 production may be enhanced or reduced by different cytokines at concentrations likely to be found in chronic inflammatory lesions.     

Comparative study of cytokine release by human peripheral blood mononuclear cells stimulated with Streptococcus pyogenes superantigenic erythrogenic toxins, heat-killed streptococci, and lipopolysaccharide.

The differences between toxic or septic shocks in humans during infections by streptococci and gram-negative bacteria remain to be fully characterized. For this purpose, a quantitative study of the cytokine-inducing capacity of Streptococcus pyogenes erythrogenic (pyrogenic) exotoxins (ETs) A and C, heat-killed S. pyogenes bacteria, and Neisseria meningitidis endotoxin (lipopolysaccharide [LPS]) on human peripheral blood mononuclear cells (PBMC) and monocytes has been undertaken. The levels of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), and TNF-beta induced by these bacterial products and bacteria were determined by using cell supernatants. The capacity of ETs to elicit the monocyte-derived cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha was found to depend on the presence of T lymphocytes, because of the failure of purified monocytes to produce significant amounts of these cytokines in response to ETs. PMBC elicited large amounts of these cytokines, as well as IL-8 and TNF-beta, with an optimal release after 48 to 96 h. The most abundant cytokine produced in response to ETA was IL-8. In contrast to the superantigens ETA and ETC, LPS and heat-killed streptococci stimulated the production of significant amounts of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha, with optimal production after 24 to 48 h in monocytes, indicating no significant involvement of T cells in the process. ETs, but neither LPS nor streptococci, were potent inducers of TNF-beta in PBMC. This study outlines the differences in the pathophysiological features of shock evoked by endotoxins and superantigens during infection by gram-negative bacteria and group A streptococci, respectively. The production of TNF-alpha was a common pathway for LPS, streptococcal cells, and ETs, although cell requirements and kinetics of cytokine release were different.     

IL-24 modulates IFN-gamma expression in patients with tuberculosis

IL-24 is a newly described member of the IL-10 family. We previously demonstrated that PBMC from TB patients exhibited low levels of IL-24 and IFN-gamma compared to subjects with latent tuberculosis infection (LTBI). In order to investigate the role of IL-24 in IFN-gamma expression in TB patients, we stimulated PBMC from individuals with LTBI or TB patients with the Mtb-specific antigen, early secretory antigenic target-6 (ESAT-6) and measured cytokine expression using quantitative real-time PCR (qPCR). Exogenous IL-24 increased IFN-gamma expression in PBMC obtained from TB patients while neutralization of IL-24 reduced IFN-gamma expression in PBMC from subjects with LTBI. Exogenous IL-24 enhanced IFN-gamma expression by increasing expression of IL-12 family cytokines, including IL-12alpha, IL-12beta, IL-23alpha and IL-27, and by reducing FOXP3 expression in PBMC from TB patients. This is the first demonstration that IL-24 may play an important role in IFN-gamma expression following infection with Mtb.     

IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis

Although a defective Th1 response has been demonstrated in patients infected with Mycobacterium tuberculosis (Mtb), the mechanisms leading to this defect are not well understood. To study the immune response to Mtb infection, we stimulated PBMC from individuals with latent tuberculosis infection (LTBI) or patients with tuberculosis (TB) with the Mtb specific antigen early secretory antigenic target-6 (ESAT-6). mRNAs for a panel of cytokines were measured using quantitative real-time PCR (qPCR). PBMC from TB patients exhibited low levels of IFN-gamma, IL-12alpha, IL-12beta, and IL-23 mRNA but high levels of IL-9 mRNA. Sera from TB patients blocked the differentiation and function of dendritic cells from TST negative (TST-) donors. Exogenous IL-9 reduced IFN-gamma mRNA expression in PBMC from LTBI by 30% (n=4) and neutralization of IL-9 restored the IFN-gamma mRNA expression in PBMC from TB patients by 66% (n=8). Thus, increased expression of IL-9 may contribute to the development of TB.     

In vitro cytokine production by normal human peripheral blood mononuclear cells as a measure of immunocompetence or the state of activation.

Measurements of cytokine levels in serum may not adequately reflect the cytokine-producing potential of immune cells because of the short half-lives of cytokines and the presence of various inhibitors in human sera. In vitro cytokine production by peripheral blood mononuclear cells (PBMCs) can be an important and reliable measure of immunocompetence. Also, spontaneous in vitro release of cytokines by PBMCs may serve as a measure of their activation in vivo. In the present study, normal ranges for the in vitro production by PBMCs of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), IL-2, and gamma interferon (IFN-gamma) were established; the feasibility of using cryopreserved PBMCs for assays of in vitro cytokine production was evaluated; and spontaneous (unstimulated) versus induced production of cytokines by fresh and cryopreserved PBMCs from healthy donors was compared. Supernatants obtained from paired fresh and frozen PBMCs were quantitated for IL-1 beta, TNF-alpha, IL-2, and IFN-gamma by using enzyme-linked immunosorbent assay or a radioimmunoassay standardized against World Health Organization cytokine standards. Fresh or cryopreserved PBMCs activated with lipopolysaccharide produced comparable levels of IL-1 beta. However, the mean levels of stimulated production of TNF-alpha, IFN-gamma, and IL-2 were significantly higher in cryopreserved versus fresh PBMCs (P < or = 0.0004). Correlations between the level of production of each cytokine by fresh versus cryopreserved in vitro-stimulated PBMCs were statistically significant, although of moderate magnitude. Spontaneous cytokine release by fresh versus cryopreserved cells was not significantly different.     

Beta2-adrenergic receptors mediate the differential effects of catecholamines on cytokine production of PBMC.

We determined characteristics of beta2-adrenergic receptors (beta2R) on peripheral blood mononuclear cells (PBMC) and cytokine production after mitogenic stimulation and coincubation with catecholamines. PBMCs were stimulated with interleukin-2 (IL-2), tetanus toxoid (TT), anti-CD3 antibody, or phytohemagglutinin (PHA). The cytokines interferon-gamma (IFN-gamma), IL-4, and IL-6 were determined by ELISA following coincubation with high-dose (10(-5) M) and low-dose (10(-9) M) epinephrine (EPI) and norepinephrine (NE). Intracellular IFN-gamma and IL-4 were studied by FACS analysis. The beta2R density was investigated using a radioligand binding assay. The stimuli induced various cytokine profiles in PBMCs. Synthesis of IFN-gamma was induced by all mitogens and could be suppressed by catecholamines (26%-85% reduction). In PHA-stimulated PBMCs, IL-4 synthesis was decreased by high-dose catecholamines (24%-28% reduction). Adding a beta-blocking agent attenuated most catecholamine effects. A highly significant negative correlation between the density of beta2R with IFN-gamma and IL-6 levels of PHA-activated PBMCs (r = -0.88 to -0.96, p < 0.01-< 0.001) was observed. The results indicate that the density of beta2R on PBMC plays a role in mediating the differential catecholamine effects on cytokine production of PBMC. Furthermore, changes in cytokine expression induced by catecholamines favor Th2 responses.     

Temporal relationship of cytokine release by peripheral blood mononuclear cells stimulated by the streptococcal superantigen pep M5.

We undertook this study to determine the quality, quantity, and temporal relationship of pep M5-induced cytokine release. The ability of pep M5 to stimulate interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) production by a T-cell-depleted, monocyte- and B-cell-enriched cell population was dependent on the presence of T cells. The requirement for T cells could be met by addition of exogenous gamma interferon (IFN-gamma). In the presence of IFN-gamma, pep M5 induced the release of TNF-alpha, IL-1, and IL-6, TNF-alpha levels peaked at 24 h, while IL-1 and IL-6 levels peaked at 48 h. pep M5 induced T cells to produce IFN-gamma, which may have accounted for the ability of the super antigen to induce the production of IL-1, IL-6, TNF-alpha, and TNF-beta by peripheral blood mononuclear cells (PBMC). The addition of excess IFN-gamma to cultures of pep M5 and PBMC did not further increase the release of these cytokines at 24 and 48 h but resulted in sustained higher levels at 72 h. Interestingly, TNF-beta production occurred only in the presence of pep M5 and exogenous IFN-gamma. The ability of pep M5 to induce cytokine production was compared with that of a potent super antigen, staphylococcal enterotoxin B (SEB). SEB was a 2- to 14-fold-more-potent inducer of IFN-gamma production. Furthermore, the profile of cytokine released by PBMC in response to this super antigen mimicked that seen with pep M5 in the presence of exogenous IFN-gamma. In conclusion, pep M5 induces the production of cytokines that are involved in immune regulation and inflammation. These cytokines also play a major role in human T-cell responses to this super antigen.     

Insulin-like growth factor-I stimulates IL-10 production in human T cells

There is vast body of evidence that the insulin-like growth factor (IGF)-I exerts immunomodulatory effects in vitro and in vivo. In vitro studies indicate that stimulatory effects of IGF-I may be exerted through augmentation of inflammatory cytokine production. To further explore the immunomodulatory effects of IGF-I through regulation of cytokine production, we tested the in vitro effects of IGF-I on the secretion of inflammatory T helper cell type 1 (Th1) and Th2 cytokines by human peripheral blood mononuclear cells (PBMC). To this end, PBMC were stimulated with the T cell mitogen phytohemagglutinin (PHA), and cytokines in the culture media were assessed after 18, 42, 66, and 80 h of culture. We found that IGF-I stimulated the secretion of the Th2 cytokine interleukin (IL)-10 by 40-70% in PHA-stimulated PBMC. In addition, we observed a small stimulatory effect (15%) on the secretion of another Th2 cytokine IL-4. The secretion of IL-2, IL-5, IL-6, interferon-gamma, and the inflammatory cytokines IL-1beta, IL-8, and tumor necrosis factor alpha was not or was hardly affected. IL-10 secretion was also stimulated in purified T cells, and we established that IGF-I also stimulated IL-10 mRNA expression by 100-150%. The monocyte-activating bacterial cell-wall product lipopolysaccharide induced IL-10 production in PBMC, but this was not affected by IGF-I. As IL-10 predominantly exerts anti-inflammatory actions and suppresses Th1-dependent immune responses, our results indicate that IGF-I may exert inhibitory actions on inflammatory and Th1-mediated cellular immune responses through stimulation of IL-10 production in T cells.     

Dexamethasone promotes type 2 cytokine production primarily through inhibition of type 1 cytokines.

Glucocorticoids, at concentrations mimicking stress-physiologic plasma levels, cause an in vitro shift in the type 1/type 2 cytokine balance of human peripheral blood mononuclear cells (PBMC) toward a predominant type 2 response. The mechanisms of these immune alterations are currently unknown but may involve modulation of key cytokines known to regulate the type 1/type 2 cytokine balance. Therefore, we sought to determine the role of cytokines previously reported to regulate the type 1/type 2 cytokine balance, including interleukin-12 (IL-12), interferon-gamma (IFN-gamma, IL-10, IL-4, and IL-13, in the glucocorticoid-mediated human type 1/type 2 cytokine alterations. Human PBMC were stimulated in vitro with tetanus toxoid in the presence of 10(-8) M dexamethasone (DEX). Cultures were supplemented with recombinant human (rHuIL-12), rHuIFN-gamma, or neutralizing monoclonal antibodies (mAb) against IL-4, IL-10, or IL-13. DEX decreased IFN-gamma production and increased IL-4 and IL-10 production by tetanus-stimulated PBMC. The addition of either recombinant IL-12p70 or IFN-gamma abrogated the DEX-mediated decrease in IFN-gamma and increase in IL-4 production. Neutralization of IL-4 activity partially abrogated the DEX-induced alterations in IFN-gamma and IL-4, but not IL-10, production. Neutralization of IL-10 or IL-13 had no effect on the Dex-mediated type 1/type 2 cytokine alterations. Therefore, the DEX-mediated type 1/type 2 cytokine alterations in tetanus-stimulated PBMC are primarily the result of downregulation of type 1 cytokines, subsequently permitting the production of type 2 cytokines.     

Effects of interferons alpha and gamma on cytokine production and phenotypic pattern of human bronchial epithelial cells

Human bronchial epithelial cells are involved in airway immune mechanisms through secretion of cytokines and through cell-cell contacts with immunocompetent cells. The aim of our study was to assess the ability of interferon (IFN) alpha and gamma alone and in combination to modulate human bronchial epithelial cell (HBECs) release of the inflammatory cytokines IL-8 and IL-6 and fibronectin and to induce the surface expression of HLA-DR and ICAM-1 molecules involved in immune interactions with other cells. HBECs spontaneously secreted a limited amount of IL-8, which was significantly increased by IFN gamma. IFN alpha inhibited IFN gamma stimulated IL-8 secretion in a concentration-dependent manner. Further, IFN gamma induced IL-6 and fibronectin secretion, and this was also inhibited by IFN alpha. The expression of HLA-DR antigens was significantly increased by IFN gamma and partially inhibited by co-stimulation with IFN alpha. In contrast, IFN gamma also induced ICAM-1 expression by HBECs but co-stimulation with IFN alpha had no significant effect on the expression of this surface antigen. IFN alpha modulation of HBEC functions does not seem to be restricted to IFN gamma stimulation since either stimulatory or inhibitory effects of INF alpha on IL-8 production have been found in pilot experiments using IL-1 beta, TNF alpha, and TGF beta as stimuli. In summary, IFN-gamma induces a number of responses in HBECs including increased secretion of IL-6, IL-8 and fibronectin and increased expression of HLA-DR and ICAM-1. IFN alpha can inhibit all these except expression of ICAM-1 which is unaffected. IFN alpha can also interact with other inflammatory cytokines, but whether the effects are inhibitory or augmentive depends on the cytokines.