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The Journal of Immunology, 1998, 161: 2011-2018.
Copyright © 1998 by The American Association of Immunologists

IFN-{alpha} Priming of Human Monocytes Differentially Regulates Gram-Positive and Gram-Negative Bacteria-Induced IL-10 Release and Selectively Enhances IL-12p70, CD80, and MHC Class I Expression1

Patrice Hermann*, Manuel Rubio*, Toshi Nakajima{dagger}, Guy Delespesse* and Marika Sarfati2,*

* University of Montreal, Louis-Charles Simard Research Center, Notre-Dame Hospital, Montreal, Canada; and {dagger} Department of Bioregulatory Function, Faculty of Medicine, University of Tokyo, Tokyo, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Administration of IFN-{gamma} and IFN-{alpha} may protect or induce autoimmune diseases. Although the in vitro regulation of monokine secretion by IFN-{gamma} have been extensively studied, the regulatory function of IFN-{alpha} has not yet been elucidated. We compared IFN-{alpha} and IFN-{gamma}, added alone or simultaneously before bacterial stimulation, for the control of monokine release and the expression of costimulatory molecules by human monocytes. Our data show that: 1) IFN-{alpha} primes monocytes for increased production of IL-10 in response to Staphylococcus aureus Cowan I strain (SAC) but not to LPS, leading to a lack of IFN-{alpha} priming for TNF-{alpha} secretion; 2) pretreatment of monocytes with IFN-{alpha} inhibits LPS- or SAC-induced IL-12p40 production but unexpectedly enhances the release of the biologically active form of IL-12 (IL-12p70); 3) IFN-{alpha} and IFN-{gamma} exert an antagonistic effect on LPS- and SAC-induced IL-10 as well as IL-12p40 release, whereas they further enhance IL-12p70 production when added simultaneously; 4) in contrast to IFN-{alpha}, IFN-{gamma} primes monocytes to enhance LPS- or SAC-induced TNF-{alpha} and IL-12 production, but surprisingly, it increases IL-10 production by monocytes following LPS but not SAC stimulation; and finally, 5) IFN-{alpha} pretreatment selectively up-regulates CD80 and MHC class I expression on monocytes. It is proposed that the outcome of the immune response at the site of inflammation may depend on both the type of bacterial injury (Gram-positive or -negative) and of locally produced IFNs, and that the differential and opposite effects of type I and type II IFNs on monocytes may account for the beneficial or detrimental effects of IFN-{alpha} therapy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Interferons are classified in two different sets of five families of proteins: type I IFNs (IFN-{alpha}, IFN-ß, IFN-{omega}, and IFN-{tau}), which are encoded by over 20 intronless genes, and type II IFN, which includes one structurally different single gene-encoded protein, namely IFN-{gamma} (1). Whereas the biologically active factors belonging to type I IFN share the same multimeric receptor (2, 3), IFN-{gamma} utilizes its own receptor complex (4, 5). Both IFN membrane receptor complexes transduce signals to intracellular compartments via the Janus kinase (Jak)3-STAT signal transduction pathway (6, 7). However, they share only Jak-1 and one signal transducer and activator of transcription (STAT1ß or STAT 91). Type I IFNs are commonly defined as antiviral agents displaying restricted immunomodulatory functions, whereas IFN-{gamma} is a well-known immunomodulatory cytokine endowed with little antiviral activities. Nevertheless, they share some biologic activities, such as the ability to increase the recruitment of cytotoxic T cells, NK cells, and phagocytes directed against virus-infected cells, tumor Ag-bearing cells, or parasite-infected cells. This common effect seems to be related to MHC class I-enhanced expression by IFN-treated APC (8). Moreover, IFN-{alpha} and IFN-{gamma} inhibit IL-4-induced soluble CD23 and IgE synthesis by human lymphocytes (9, 10). Both IFNs appear to favor Th1 development as well as Th1 response in human and murine cells (11, 12, 13, 14). More precisely, priming of naive T cells with IFN-{alpha} promotes Th1 phenotype by decreasing IL-4 and IL-5 and by increasing IFN-{gamma} production (12, 13). Interestingly, IFN-{alpha} but not IFN-{gamma} stimulates T cells for increased IL-10 production, a property shared by IL-12, which is the best Th1-promoting cytokine (12, 15, 16, 17). Also, the addition of IFN-{alpha}, IFN-{gamma}, or IL-12 to Ag-stimulated human PBMC polarizes the immune response toward a type 1 cytokine profile (15, 17, 18, 19, 20, 21).

Type I and II IFNs, however, exert differential activities on monocytes. IFN-{gamma} is a proinflammatory cytokine in that it stimulates TNF-{alpha} production, inhibits IL-10 release, and primes monocytes to further enhance bacteria-induced IL-12 (22, 23, 24, 25) as well as TNF-{alpha} release (26). In contrast, IFN-{alpha} displays mainly anti-inflammatory activities; it enhances IL-10 production by activated macrophages, while decreasing IL-8 and GM-CSF secretion (15, 27, 28). Of note, type I IFNs may behave as a proinflammatory molecule, since they have been reported to stimulate B cells, T cells, and monocytes to secrete ISG15, an IFN-{gamma}-inducing factor (29). Although type I IFNs are used clinically to treat patients suffering from type 1 autoimmune diseases such as multiple sclerosis, their precise mode of action has not yet been elucidated (30).

The aim of the present study was to examine the ability of IFN-{alpha} to regulate the production of proinflammatory (TNF-{alpha}, IL-12) and anti-inflammatory (IL-10) cytokines by human monocytes stimulated with bacterial products. Three considerations prompted us to compare IFN-{alpha} with IFN-{gamma}: 1) the effects of IFN-{gamma} in this system have been well documented, and IFN-{gamma} may therefore serve as a reference (22, 23, 24, 25, 31); 2) IFN-{gamma} shares a number of important properties with IFN-{alpha} including the ability to promote Th1 and inhibit Th2 responses (11, 12, 13); and 3) although the receptor for IFN-{gamma} is entirely distinct from that of IFN-{alpha}, the signaling molecules Jak-1 and STAT1ß are used by both cytokines, and STAT1-deficient cells are unresponsive to the two types of IFNs (4, 5, 6, 7, 32).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents

Human recombinant IFN-{gamma} and -{alpha} were purchased from Genzyme (Boston, MA). Staphylococcus aureus Cowan 1 strain (SAC) was used at 1/10000 dilution (Pansorbin; Calbiochem-Behring, La Jolla, CA) and LPS at 10 µg/ml (from Escherichia coli, serotype 0111:B4; Sigma Chemical, St. Louis, MO). Neutralizing anti-human IL-10 mAb (clone 19F1.1) was used at 10 µg/ml and was purchased from American Type Culture Collection (ATCC, Manassas, VA). FITC-conjugated mAb against CD14 and MHC class I (HLA-A, -B, and -C) were obtained, respectively, from Becton Dickinson and Ancell (London, Ontario, Canada). Phycoerythrin-conjugated mouse anti-human CD54 and MHC class II (HLA-DP, -DQ, and -DR) mAb and nonconjugated anti-CD80 and anti-CD86 were from Ancell. Unconjugated anti-CD58 was from ATCC (clone TS2/9.1.4.3), and unconjugated anti-CD40 (mAb89) was kindly provided by Dr. J. Banchereau (Schering-Plough, Dardilly, France).

Cell preparation and culture conditions

Peripheral blood monocytes (>95% CD14+) were purified as previously described (33). Briefly, PBMC isolated from healthy donors by Ficoll-Hypaque centrifugation were cold aggregated and further depleted from T and NK cells by rosetting with 5-(2-aminoethyl)isothrouronium bromide (Aldrich Chemical, Milwaukee, WI)-treated SRBC.

All cultures were performed in serum-free HB101 medium (Irvine Scientific, Santa Ana, CA) supplemented with 2 mM glutamine, 1 mM sodium pyruvate, 10 mM HEPES, 100 IU of penicillin, and 100 µg/ml streptomycin. Enriched monocytes (2 x 105 cells for TNF-{alpha} or 5 x 105 for IL-12p40, IL-12p70, and IL-10 production) were primed in 5-ml polystyrene tubes (Falcon Labware, Oxnard, CA) overnight at 37°C in 500 µl of HB101 complete medium containing 10 µg/ml polymyxin B, with or without 500 IU/ml IFN-{gamma} and/or 2500 IU/ml IFN-{alpha}. Cells were then washed once in HBSS (BioWhittaker, Walkersville, MD) and stimulated with SAC or LPS in 1 ml of culture medium. Culture supernatants were harvested after 24 h for the measurement of TNF-{alpha} and after 48 h for the measurement of IL-12p40, p70, and IL-10. In selected experiments, rat anti-human IL-10 mAb or isotype-matched control rat mAb were used at 10 µg/ml during both priming and stimulation.

Cytokine measurement

TNF-{alpha} was measured using a sandwich ELISA as previously described (34). IL-10 was determined by a sandwich solid phase RIA using anti-human IL-10 mouse mAb (clone 9D7) to coat the solid phase and 125I-labeled mouse anti-human IL-10 mAb (clone 12G8) as a detecting probe. IL-12p40 and IL-12p70 heterodimer were measured with two different specific ELISAs using either anti-IL-12p40 mAb (clone 2.4A1) or anti-complex IL-12p40/p35 mAb (clone 20C2) as capture Abs together with anti-IL-12p40 mAb (clone 4D6) as a common second Ab (33). Anti-IL-12 mAbs were kindly provided by Dr. M. Gately (Hoffmann-La Roche, Nutley, NJ). The sensitivity of the assays was 50 pg/ml for TNF-{alpha} and IL-10 and 10 pg/ml for both IL-12p40 and p70.

Northern blot analysis

Total RNA was isolated using the RNeasy Mini Kit (Qiagen, Santa Clarita, CA). Fifteen micrograms of RNA per condition were resolved using 1% formaldehyde agarose gel and blotted on pure nitrocellulose membrane filter (Schleicher and Schuell, Keene, NH) followed by UV cross-linking for immobilization. Membranes were probed under a 50% formamide-based hybridization buffer also containing 5x sodium saline citrate, 10% dextran sulfate, 1x Denhardt’s solution, 20 mM Tris, pH 7.5, 100 µg/ml denatured salmon sperm DNA, and 0.5% SDS, then washed for 2 h at 65°C under high stringency (0.1x SSC, 0.1% SDS) before autoradiography. Human IL-12p35 and p40 cDNA probes, kindly provided by U. Gubler (Hoffmann-LaRoche), were labeled with [{alpha}-32P]dCTP using a commercial random oligolabeling kit (Pharmacia Biotech, Uppsala, Sweden). A cDNA probe specific for ß-actin was used as a control to normalize the quantification. Radioactivity was determined by autoradiography of nitrocellulose membranes and analyzed by computer imaging (NIH Image 1.61, National Institutes of Health, Bethesda, MD).

Flow cytometry analysis

Enriched monocytes were cultured overnight at 2.105 cells/vials in 500 µl of HB101 complete medium containing 10 µg/ml of polymyxin B in the absence or presence of IFN-{alpha} or/and IFN-{gamma}. Cells were then stained with the indicated mAb according to standard techniques in the presence of normal human Ig (150 µg/ml) and analyzed using a FACScan (Becton Dickinson, Mountain View, CA). For unconjugated mAb, an additional step of staining using a FITC-conjugated F(ab')2 fragment of goat anti-mouse Abs (Ancell) was performed following the manufacturer’s instructions. Results are expressed as {Delta} median fluorescence intensity ({Delta}MFI), which represent the median fluorescence intensity of cells labeled with Abs of interest minus the median fluorescence intensity of cells stained with isotype-matched control Abs.

Statistical analysis

Results are expressed as the mean ± SEM of n independent experiments. Statistical significance was determined by using Student’s paired t test, when n >= 5; or the Wilcoxon-Mann-Whitney test, when n = 3. Significant values are shown in figures as **** for p <= 0.0001, *** for p <= 0.001, ** for p <= 0.01, and * for p <= 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Differential effect of IFN-{alpha} and IFN-{gamma} priming on TNF-{alpha} and IL-10 production in response to bacterial stimuli

Previous reports have indicated that LPS-induced IL-10 production by human monocytes was suppressed by IFN-{gamma}, leading to enhanced TNF-{alpha} production, and that IFN-{alpha} enhanced bacteria-induced IL-10 (15, 22, 26). Here, we first show that pretreatment of monocytes with IFN-{alpha} for >=20 h significantly inhibits LPS-induced TNF-{alpha} release (Fig. 1GoA, p = 0.018), whereas it fails to regulate LPS-induced IL-10 secretion (Fig. 1GoB). In contrast, priming with IFN-{gamma} significantly enhances LPS-induced IL-10 and TNF-{alpha} production (Fig. 1GoA, p = 0.017; Fig. 1GoB, p = 0.015; Fig. 2GoA). Most strikingly, IFN-{alpha} completely abrogates, in a dose-dependent manner, the effect of IFN-{gamma} priming on IL-10 production (Fig. 1BGo, p = 0.033; Fig. 2GoB), whereas IFN-{gamma} and IFN-{alpha} antagonize each other with regard to TNF-{alpha} production (Fig. 1GoA, p = 0.043 and 0.009).



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  		FIGURE 1. Effect of IFN-{alpha} and IFN-{gamma} priming on LPS- or SAC-induced TNF-{alpha} and IL-10 production. Enriched monocytes were primed as indicated in the presence of IFN-{alpha} and/or IFN-{gamma} and stimulated by LPS (A and B) or SAC (C and D). TNF-{alpha} (A and C) and IL-10 (B and D) were measured in culture supernatant after 24 or 48 h, respectively. Shown are the means ± SEM of 4 representative experiments of 12. Statistical analysis was performed on 12 experiments.

 


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  		FIGURE 2. Dose-dependent effect of IFN-{alpha} and IFN-{gamma} on LPS- or SAC-induced IL-10 production. Enriched monocytes were primed overnight in the presence of various concentrations of IFN-{gamma} alone (A), 500 IU of IFN-{gamma}/ml, and variable amounts of IFN-{alpha} (B), various concentrations of IFN-{alpha} alone (C), or 2500 IU of IFN-{alpha}/ml and variable amounts of IFN-{gamma} (D). Cells were then washed and stimulated for 48 h by either LPS (A and B) or SAC (C and D). Results show one representative experiment of three.

 
We next examined whether the lack of an IFN-{alpha} priming effect on monokine production was also observed in response to SAC, another commonly used bacterial stimulus. Surprisingly, we found that IFN-{alpha} does not prime for TNF-{alpha} (Fig. 1GoC) but strongly enhances IL-10 production (Fig. 1GoD, p = 0.0008); this effect is dose dependent (Fig. 2GoC). Conversely, IFN-{gamma} primes monocytes for TNF-{alpha} production (Fig. 1GoC, p = 0.011) and fails to prime for IL-10 secretion (Fig. 1GoD). Furthermore, we observed that, as described for LPS, IFN-{alpha} significantly antagonizes the IFN-{gamma} priming effect on TNF-{alpha} release (Fig. 1GoC), whereas IFN-{gamma} completely suppresses the IFN-{alpha} priming effect on IL-10 production (Fig. 1GoD, p = 0.002); this inhibitory effect is dose-dependent (Fig. 2GoD). Of note, IFN-{alpha}, IFN-{gamma}, or IFN-{alpha} plus IFN-{gamma} priming completely fails to trigger monokine release in the absence of subsequent bacterial (i.e., LPS or SAC) stimulation (data not shown).

These data demonstrate that: 1) pretreatment of monocytes with IFN-{alpha} alone supresses or fails to increase TNF-{alpha} production, while addition of IFN-{gamma} significantly reverses this suppressive effect; and 2) IFN-{alpha} and IFN-{gamma}, added at priming, differentially regulate and more strikingly display antagonistic effects on IL-10 production in response to LPS or SAC.

Role of endogeneous IL-10 in the failure of IFN-{alpha} to prime for TNF-{alpha} production

IL-10 has been described as an inhibitory factor for TNF-{alpha} release by activated monocytes (35). According to our preliminary kinetic studies, TNF-{alpha} and IL-10 are optimally detected after 24 and 48 h of monocyte stimulation, respectively. Because IFN-{alpha} significantly primes for IL-10 in response to SAC but not LPS (Fig. 1Go, B and D), we examined whether the absence of IFN-{alpha} priming on TNF-{alpha} secretion in SAC-stimulated monocytes (Fig. 1GoC) may be explained by its strong induction of IL-10 release (Fig. 1GoD). As shown in Table IGo, pretreatment with IFN-{alpha} in the presence of anti-IL-10 mAb significantly increases SAC-induced TNF-{alpha} production (Table IGo; p = 0.031), almost to the same extent as IFN-{gamma} priming. As expected, addition of anti-IL-10 mAb during IFN-{alpha} priming does not enhance LPS-induced TNF-{alpha} release, while it significantly increases the priming effect of IFN-{gamma}, further supporting the above data that IFN-{gamma} but not IFN-{alpha} priming increases LPS-induced IL-10 production (Fig. 1GoB).


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  		Table I. Regulatory role of endogenous IL-10 on bacteria-induced TNF-{alpha} production1

 
We conclude that the lack of IFN-{alpha} priming on TNF-{alpha} production by SAC-stimulated monocytes is IL-10 dependent, whereas its inability to enhance LPS-induced TNF-{alpha} production is IL-10 independent.

Differential effect of IFN-{alpha} and IFN-{gamma} on IL-12p40 and IL-12p70 release

IL-10 was also reported to be a potent regulator of IL-12 production by activated monocytes (36). We therefore examined whether IFN-{alpha} may differentially regulate LPS- or SAC-induced IL-12 release. Because the production of IL-12p70 has been described as generally following that of IL-12p40, we first measure IL-12p40 in 48-h culture supernatants. Surprisingly, IFN-{alpha} priming significantly inhibits both LPS- and SAC-induced IL-12p40 (Fig. 3GoA, p = 0.002; Fig. 3GoB, p = 0.012). Furthermore, IFN-{alpha} strongly suppresses the IFN-{gamma} enhancement of IL-12p40 production in response to both stimuli (Fig. 3GoA, p = 0.0003; Fig. 3GoB, p < 0.0001).



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  		FIGURE 3. Effect of IFN-{alpha} and IFN-{gamma} priming on IL-12p40 production. Enriched monocytes were primed and further stimulated by either LPS (A) or SAC (B) as indicated in the legend to Figure 1Go. IL-12p40 was measured after 48 h of stimulation. Shown are the means ± SEM of 12 independent experiments.

 
According to data described in Figure 1Go, B and D, indicating that IFN-{alpha} and IFN-{gamma} added together completely antagonized each other for IL-10 production in response to both LPS and SAC, we postulated that the opposite effect of IFN-{alpha} and IFN-{gamma} on IL-12p40 release was not mediated by IL-10. This hypothesis was confirmed by showing that the antagonism between IFN-{alpha} on IFN-{gamma} remains statistically significant in the presence of blocking anti-IL-10 mAb (LPS stimulation, p = 0.032; SAC stimulation, p = 0.011). However, addition of anti-IL-10 mAb abrogates the inhibitory effect of IFN-{alpha} on IL-12p40 production without conferring a priming effect (not detailed).

It is generally well accepted that IL-12p40 measurement is a good reflection of the bioactive form of IL-12 (IL-12p70). Nevertheless, Kincy-Cain and Bost have reported that substance P stimulated murine macrophages to secrete IL-12p40 but not IL-12p70 (37). We therefore compared the effect of IFN-{alpha} and IFN-{gamma} priming on the release of IL-12p70. Unexpectedly, although priming with IFN-{alpha} inhibits IL-12p40 release, it significantly enhances IL-12p70 production in both LPS- and SAC-stimulated monocytes (Fig. 4GoA, p = 0.015 ; Fig. 4GoB, p = 0.016), albeit to a lesser extent than IFN-{gamma} (Fig. 4GoA, p = 0.0001; Fig. 4GoB, p = 0.011).



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  		FIGURE 4. Effect of IFN-{alpha} and IFN-{gamma} priming on IL-12p70 production. Enriched monocytes were primed as indicated and further stimulated by either LPS (A) or SAC (B). IL-12p70 release was determined in culture supernatants after 48 h of stimulation. Neutralizing anti-IL-10 or isotype-matched mAb (at 10 µg/ml each) were added during priming and stimulation. Shown are the means ± SEM of five independent experiments.

 
The addition of anti-IL-10 mAb increases IL-12p70 production as well as the priming effect of IFN-{alpha} and IFN-{gamma}, respectively. It is worth noting that in response to LPS, the enhancing effect of IFN-{gamma} remains higher than that of IFN-{alpha}, while in response to SAC, both priming effects are similar, further supporting the above data that 1) IFN-{gamma} primes monocytes to increase IL-10 release in response to LPS (Fig. 1GoB) and not SAC (Fig. 1GoD); and 2) IFN-{alpha} primes monocytes to increase IL-10 release in response to SAC (Fig. 1GoD) and not LPS (Fig. 1GoB).

The data in Figure 5Go further indicate that IFN-{alpha} significantly increases, in a dose-dependent manner, the IFN-{gamma}-priming effect on LPS-induced IL-12p70 production, while in the same culture supernatants, it antagonizes the IFN-{gamma}-enhancing effect on IL-12p40 production. To investigate some of the mechanisms underlying the opposite effect of IFN-{alpha} on LPS-induced IL-12p40 and IL-12p70 protein release, we examined the regulatory effect of IFN-{alpha} on the accumulation of IL-12p35 and IL-12p40 mRNA. Northern blot analysis (Fig. 6Go) shows that 1) IFN-{gamma} primes monocytes for enhanced LPS-induced IL-12p40 (6-fold) and IL-12p35 (3-fold) mRNA, as reported by several investigators (25, 31). Note that we failed to detect LPS-induced IL-12p35 mRNA using this technique under serum-free medium culture conditions; 2) IFN-{alpha} priming decreases IL-12p40 steady state mRNA level and IL-12p40 secretion, with no detectable induction in IL-12p35 mRNA, but with an enhancement of IL-12p70 release; and 3) priming with IFN-{alpha} does not modulate the regulatory priming effect of IFN-{gamma} on IL-12p35 mRNA, whereas it decreases IFN-{gamma}-induced IL-12p40 mRNA. As clearly shown in this figure, there is a discrepancy between the modest (i.e., IFN-{alpha}, 2.2-fold) to large increase (IFN-{alpha} plus IFN-{gamma}, 24.7-fold) in IL-12p70 protein release in response to LPS and the absence of regulation of IL-12p35 mRNA transcripts, suggesting posttranscriptional regulatory mechanisms by IFN-{alpha} for IL-12p35 expression.



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  		FIGURE 5. Dose-dependent effect of IFN-{alpha} on IFN-{gamma} enhancement of LPS-induced IL-12-p40 and p70 production. Enriched monocytes were primed in the presence of 500 IU of IFN-{gamma}/ml and various concentrations of IFN-{alpha}, then further stimulated by LPS. IL-12-p40 and IL-12p70 were measured after 48 h of stimulation. Shown are the results of one representative experiment of three.

 


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  		FIGURE 6. Effect of IFN-{alpha} and/or IFN-{gamma} priming on IL-12p35 and p40 mRNA accumulation. Monocytes were primed overnight in medium alone (lane 1), IFN-{alpha} (lane 2), IFN-{gamma} (lane 3), or IFN-{alpha} and IFN-{gamma} (lane 4), followed by stimulation with LPS for 6 h for total RNA analysis or 48 h for protein production in culture supernatant. Northern blots were first probed as described in Materials and Methods using a specific human IL-12p35 cDNA probe, then stripped and reprobed with specific human IL-12p40 and ß-actin cDNA probes successively. The relative induction of IL-12p35 and p40 mRNA steady state were determined by computer imaging after normalization using ß-actin detection, then compared with relative induction of IL-12p70 and p40 protein release, respectively. Since the p35 subunit of IL-12 is not detectable in culture supernatant, quantification of IL-12p70 heterodimers was used to estimate p35 protein release. Shown is one representative experiment of three.

 
Differential effect of IFN-{alpha} and IFN-{gamma} on the expression of accessory molecules by human monocytes

Our results indicate that IFN type I and type II possess differential and antagonistic effects when added at priming on both LPS- or SAC-induced TNF-{alpha}, IL-12p40, and IL-10 release. We therefore examined whether these differential effects could also be observed on the expression of surface molecules implicated in Ag presentation and T cell activation. To address this question, enriched monocytes were primed in presence of IFN-{gamma}, IFN-{alpha}, or both and analyzed for the expression of different Ags as indicated in Figure 7Go. The results show that IFN-{alpha} selectively enhances the expression of MHC class I as well as CD80 molecules on monocytes (Fig. 7GoB), whereas it augments the IFN-{gamma}-induced up-regulation of CD40 and MHC class I. However, stimulation of monocytes with IFN-{gamma} but not IFN-{alpha} up-regulates the expression of MHC class II, CD40, CD86, and CD54 (Fig. 7GoA). Of interest, IFN-{gamma} decreases CD14 expression.



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  		FIGURE 7. Effect of IFN-{alpha} and/or IFN-{gamma} priming on costimulatory molecules expression. Monocytes were cultured overnight in the presence or absence of cytokines as indicated and analyzed by flow cytometry. A, {Delta} median fluorescence intensity ({Delta}MFI) as described in Materials and Methods. B, control mAb (open histograms) and CD80 or MHC class I mAbs (gray histograms). Results represent one of three independent experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study shows that treatment of monocytes with IFNs type I or II for 20 h differentially primes them for TNF-{alpha}, IL-10, and IL-12 release and that secretion of IL-12p40 may be dissociated from that of IL-12p70 under the conditions of IFN-{alpha} priming. In contrast to the well-described ability of IFN-{gamma} to prime for TNF-{alpha} and IL-12 (IL-12p40 and IL-12p70) production, priming with IFN-{alpha} before SAC stimulation significantly decreases IL-12p40, slightly enhances IL-12p70, and strongly increases IL-10 production. The weak IL-12p70 enhancement and the lack of priming for TNF-{alpha} are both explained by endogeneous IL-10 production. Indeed, in the presence of anti-IL-10 neutralizing mAb, the levels of SAC-induced IL-12p70 and TNF-{alpha} production are similar to those achieved following IFN-{gamma} priming (Table IGo and Fig. 4Go). Although the effect of pretreatment with IFN-{alpha} appears quite similar in response to LPS (i.e., inhibition of TNF-{alpha} and IL-12p40 and a weak increase in IL-12p70), these activities are largely IL-10 independent, inasmuch as IFN-{alpha} fails to prime for IL-10 production in such culture conditions. These results contrast with the enhancing effect of IFN-{alpha}, when added during stimulation, on LPS-induced IL-10 release by human monocytes (15).

As previously reported (22, 26), the addition of IFN-{gamma} during LPS stimulation inhibits IL-10 production and increases TNF-{alpha} release. In keeping with very recent studies (38), our data indicate that pretreatment of monocytes with IFN-{gamma} significantly augments LPS- but not SAC-induced IL-10 release. Of note, IFN-{gamma} priming further enhances LPS- and SAC-induced TNF-{alpha} production, and it has been reported that TNF-{alpha} may augment IL-10 secretion (39, 40). The differential ability of IFN-{alpha} and IFN-{gamma} to prime for IL-10 release according to the bacterial stimulus used is reminiscent of the observation that IL-4 consistently inhibits monokine production in response to LPS but is a less potent inhibitor or is inefficient in response to SAC (36). Note that in the latter study, it was also reported that the addition of IL-4 before bacterial stimulation primed but did not inhibit IL-12 secretion.

A striking observation of the present report is that priming with IFN-{alpha} inhibits LPS- or SAC-induced IL-12p40 release while increasing IL-12p70 secretion (Figs. 3Go and 4Go). Several inhibitors of IL-12 production by human monocytes have been described: IL-4, IL-10, TGFß, and PGE2 (41). With the exception of a few studies (37, 42), there was a constant parallelism between the level of IL-12p40 and IL-12p70 protein release. Similarly, measles virus and anti-CD46 mAb have been shown to inhibit IL-12p40 and IL-12p70 monokine production (43). Bioactive IL-12 (p70) is a heterodimer made up of two chains (IL-12p40 and IL-12p35) encoded by two distinct genes; the p40 chain is always secreted in great excess over the heterodimer (44, 45). Given that IL-12p40 (free and bound) and IL-12p70 have been detected by two specific quantitative ELISAs and that the presence of an excess amount of bioactive IL-12 (p70) did not interfere with IL-12p40 measurement and vice versa (unpublished observations), it was tempting to speculate that IFN-{alpha} differentially regulates the expression of the two IL-12 chains. First, we confirmed previous reports indicating that IFN-{gamma} priming increases LPS-induced IL-12p40 and IL-12p35 mRNA accumulation and IL-12p40 and p70 secretion (31). In contrast, IFN-{alpha} priming decreases the LPS-induced steady state IL-12p40 mRNA level, with no detectable induction of IL-12p35 mRNA. However, IFN-{alpha} priming enhances IL-12p70 protein secretion (2.2-fold increase) and decreases IL-12p40 (0.4-fold). Finally, IFN-{alpha} does not modulate the IFN-{gamma}-induced steady state IL-12p35 mRNA level, whereas it significantly enhances IFN-{gamma}-induced IL-12p70 release.

Taken together, IFN-{alpha} priming (in the presence or absence of IFN-{gamma}) increases IL-12p70 secretion and decreases IL-12p40 mRNA and protein release without regulating steady state IL-12p35 mRNA level. This suggest that IFN-{alpha} exerts translational or posttranslational regulatory mechanisms on IL-12p35 expression as previously reported for IFN-{gamma} and LPS (25). In keeping with these results, Snijders et al. provided evidence that the production of bioactive IL-12p70 in human monocytes may be determined by the expression of IL-12p35 subunit (46).

Finally, in contrast to the present report, Biron and coworkers reported that IFN-{alpha} negatively regulated IL-12 and IFN-{gamma} production in vitro as well as in vivo (47). The previously undetected early IL-12 and IFN-{gamma} production in lymphocytic choriomeningitic virus (LCMV)-infected control mice can be measured in LCMV-infected IFN-{alpha} receptor-deficient mice (48). At the present time, we do not have any explanation for these apparent contradictory results. Of interest, in those studies (47) IL-12p70 was measured by a bioassay using IFN-{gamma} production as a readout. In that regard, a novel IFN-{gamma}-inducing factor different from IL-12, namely IL-18, has been recently described (49).

IFN-{alpha} not only suppresses, in a dose-dependent manner, IFN-{gamma} priming for IL-12p40 but completely abrogates IFN-{gamma} enhancement of LPS-induced IL-10 production (Fig. 1Go). Vice versa, IFN-{gamma} totally inhibits IFN-{alpha} priming of SAC-induced IL-10 release. The antagonism between the two types of IFNs for the production of a major monocyte-deactivating factor (i.e., IL-10) is reminiscent of the report that IFN-{alpha} impaired IFN-{gamma} induction of NO synthase and release of NO (50). Also, the additive effect of both IFNs on the secretion of a proinflammatory cytokine (i.e., IL-12p70) may be biologically relevant for the observed induction of type I autoimmune disorders as a side effect of IFN-{alpha} therapy in human cancer (30). In that regard, IFN-{alpha}-transgenic mice developed a hypoinsulinemic diabetes associated with mixed inflammation that can be prevented by neutralizing Ab to IFN-{alpha} (51).

However, IFN-{alpha} therapy appears to be effective in mice for suppressing myasthenia gravis, in which it significantly decreases antiacetylcholine serum Ab levels (52). In addition, IFN-ß (which shares its receptor with IFN-{alpha}) is currently used for the treatment of patients with multiple sclerosis (53). The anti-inflammatory activity of IFN-ß was underlined by a down-regulation of TNF-{alpha} and IFN-{gamma} and by up-regulation of TGFß (30). The present data indicating that IFN-{alpha} priming increases IL-10 by monocytes, decreases TNF-{alpha}, and only slightly up-regulates biologically active IL-12, which may further up-regulates IL-10 secretion by T cells (17), would support the beneficial use of IFN-{alpha} for Th1-like disease. Nevertheless, IFN-{alpha} has also been shown to improve diseases characterized by Th2 cells, including AIDS, hypereosinophilia, and allergic diseases (30, 54). Our results showing that IFN-{alpha} increases IL-12p70 may therefore be clinically relevant, especially for AIDS patients in whom cells are inhibited in their ability to produce IL-12 (55, 56).

Finally, the present study shows that IFN-{alpha} up-regulates MHC class I with no effect on constitutive or IFN-{gamma}-induced MHC class II and selectively induces CD80 but not CD86 or CD54. Of note, Chakrabarti et al. (57) reported that IFN-{alpha} induced CD86 and CD54 in murine APC, while Ling et al. (58) showed that IFN-ß displayed an antagonistic effect on IFN-{gamma}-induced MHC class II on murine macrophages. Several reports indicated that B7 molecules (CD80 and CD86) provide the costimulation necessary for T cell proliferation and IL-12-induced IFN-{gamma} production (59). However, some publications have pointed out that CD80 stimulates a Th1 response, while CD86 favors a Th2 response (60, 61), further supporting a role for IFN-{alpha} in the induction of Th1 response (11, 12). Moreover, tumor expression of the CD80 molecule may be superior to CD86 in the activation of cytotoxic CD8+ T lymphocytes and tumor rejection (62). Therefore, the ability of IFN-{alpha} to up-regulate MHC class II and CD80 and to prime monocytes for IL-12 production may provide an additional mechanism for the antitumor activity of IFN-{alpha}.

Taken together, our present results demonstrate that IFN-{alpha} priming differentially affects monokine release in the presence or absence of IFN-{gamma}, thus underlying their beneficial or deleterious effects in various diseases according to the dose, the route, or the time of administration (1).


   Acknowledgments
 
We are most grateful to Dr. M. Gately for providing IL-12 reagents.


   Footnotes
 
1 This work was supported by Medical Research Council (MRC) Grant MT13311 and by Grant 3294 from the National Cancer Institute of Canada. M.S. is supported by an MRC Scientist Scholarship. P.H. is supported by the French Association for Cancer Research. Back

2 Address correspondence and reprint requests to Dr. M. Sarfati, University of Montreal, Louis-Charles Simard Research Center, 1560 Sherbrooke Street East, Montreal, Quebec, H2L 4 M1 Canada. Back

3 Abbreviations used in this paper: Jak, Janus kinase; SAC, Staphylococcus aureus Cowan I strain. Back

Received for publication September 8, 1997. Accepted for publication April 23, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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