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IFN- Priming Results in a Gain of Proinflammatory Function by IL-10: Implications for Systemic Lupus Erythematosus Pathogenesis¹

M. Nusrat Sharif^*, Ioannis Tassiulas^*,, Yang Hu^¶, Ingrid Mecklenbräuker, Alexander Tarakhovsky and Lionel B. Ivashkiv^2,*,,

^* Arthritis and Tissue Degeneration Program and Department of Medicine, Hospital for Special Surgery, New York, NY 10021; Laboratory of Lymphocyte Signaling, Rockefeller University, New York, NY 10021; and Graduate Programs in Immunology and ^¶ Neuroscience, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021

	Abstract

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Interleukin-10 is a predominantly anti-inflammatory cytokine that inhibits macrophage and dendritic cell function, but can acquire proinflammatory activity during immune responses. We investigated whether type I IFNs, which are elevated during infections and in autoimmune diseases, modulate the activity of IL-10. Priming of primary human macrophages with low concentrations of IFN- diminished the ability of IL-10 to suppress TNF- production. IFN- conferred a proinflammatory gain of function on IL-10, leading to IL-10 activation of expression of IFN--inducible, STAT1-dependent genes such as IFN regulatory factor 1, IFN--inducible protein-10 (CXCL10), and monokine induced by IFN- (CXCL9). IFN- priming resulted in greatly enhanced STAT1 activation in response to IL-10, and STAT1 was required for IL-10 activation of IFN--inducible protein-10 and monokine induced by IFN- expression in IFN--primed cells. In control, unprimed cells, IL-10 activation of STAT1 was suppressed by constitutive activity of protein kinase C and Src homology 2 domain-containing phosphatase 1. These results demonstrate that type I IFNs regulate the balance between IL-10 anti- and proinflammatory activity, and provide insight into molecular mechanisms that regulate IL-10 function. Gain of IL-10 proinflammatory functions may contribute to its pathogenic role in autoimmune diseases characterized by elevated type I IFN levels, such as systemic lupus erythematosus.

	Introduction

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Type I IFNs, IFN- and IFN-, are pleiotropic cytokines that are induced in many cell types by viral or bacterial products and have potent antiviral effects (1). Type I IFNs modulate many aspects of immune and inflammatory reactions (1). A key aspect of type I IFN biology is that previous exposure to IFNs alters subsequent cellular responses to extracellular stimuli. Enhancement of proinflammatory responses by previous exposure to low concentrations of type I IFNs is termed priming (2). One example is a positive feedback loop in which type I IFNs prime cells to produce large quantities of IFN- after subsequent challenge (3). Priming with type I IFNs also leads to enhanced cellular responsiveness to IFN- and IL-6 (4, 5), resulting in enhanced proinflammatory activity of these cytokines. The mechanism underlying enhanced IFN- and IL-6 responses is increased activation of STAT1, a transcription factor that is typically activated by IFN- and mediates much of its proinflammatory activity (6, 7).

One mechanism by which type I IFNs enhance STAT1 activation by IFN- or IL-6 in primed cells is to induce association of the IFN- receptor 1 (IFNAR1) subunit of the IFN receptor with IFN-R2 or with the gp130 subunit of the IL-6R in caveolar membrane domains (2). IFNAR1:IFN-R2 and IFNAR-1:gp130 interactions lead to enhanced dimerization of STATs (4, 5) that have become tyrosine phosphorylated in response to IFN- or IL-6 stimulation. An alternative, complementary mechanism of priming involves IFN-dependent increases in STAT1 expression, thus resulting in increased STAT1 interaction with receptor docking sites and increased levels of tyrosine phosphorylation when primed cells are stimulated with IFN- (8). An important component of both of these models of priming is that low concentrations of IFN preferentially activate positive feedback mechanisms (phosphorylation of IFNAR1, increased STAT1 expression), but do not engage feedback inhibitory pathways that would be activated by high concentrations of IFNs (9).

IL-10 is predominantly an immunosuppressive and anti-inflammatory cytokine that suppresses the function of dendritic cells and macrophages (10). IL-10 is a key cytokine that limits tissue injury during infections by limiting the duration and intensity of immune and inflammatory reactions. IL-10 signals by activating IL-10 receptor-associated Janus kinase 1 (Jak1)³ and tyrosine kinase 2 protein tyrosine kinases, and downstream STATs (10). In myeloid cells, IL-10 activates predominantly STAT3, and genetic and biochemical evidence show that STAT3 is required for the anti-inflammatory activity of IL-10 (11, 12). IL-10 can also exhibit proinflammatory activities, and it appears that IL-10 acquires proinflammatory activity during an active inflammatory response, such as occurs during experimental endotoxemia (13, 14), after tissue transplantation (15), and in the autoimmune disease systemic lupus erythematosus (SLE) (16). SLE is also associated with a loss of IL-10 anti-inflammatory activity (17). Interestingly, both endotoxemia and SLE are characterized by elevated production of IFN- (18, 19, 20, 21, 22, 23, 24, 25), suggesting the possibility that type I IFNs may modulate IL-10 activity in these conditions. We tested whether IFN- modulates cellular responses to IL-10, and whether this modulation may contribute to the proinflammatory activity that IL-10 acquires in an inflammatory setting.

	Materials and Methods

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Reagents and cell culture

PBMC were obtained from whole blood from disease-free volunteers by density gradient centrifugation using Ficoll (Life Technologies, Gaithersburg, MD), and monocytes (>97% CD14⁺) were purified using magnetic beads (Miltenyi Biotec, Auburn, CA), as previously described (8). Monocytes were cultured in RPMI 1640 medium (Life Technologies) supplemented with 10% FBS (HyClone Laboratories, Logan, UT). Cytokines were purchased from R&D Systems (Minneapolis, MN). Murine bone marrow-derived macrophages were generated, as previously described (26), and cells were used after 7 days of culture with 5–10 ng/ml rM-CSF. STAT1-deficient mice and genetically matched control mice and Src homology 2 domain-containing phosphatase-1 (SHP-1)-deficient motheaten mice were purchased from Taconic Farms (Germantown, NY) and The Jackson Laboratory (Bar Harbor, ME).

ELISA

Paired TNF- capture and detection Abs were purchased from R&D Systems (human TNF-) or BD PharMingen (San Diego, CA) (murine TNF-) and used in a sandwich ELISA, according to the instructions of the manufacturer.

Gene expression analysis

For real-time, quantitative PCR, 1 µg of total RNA was reverse transcribed using oligo(dT) primers and Moloney murine leukemia virus reverse transcriptase. Real-time PCR was performed in triplicate using the iCycler iQ thermal cycler and detection system (Bio-Rad, Hercules, CA), and the PCR Core Reagents kit (Applied Biosystems, Foster City, CA), with 500 nM primers; the final Mg²⁺ concentration was adjusted to 4 mM, as previously described (8). mRNA amounts were normalized relative to GAPDH mRNA.

EMSA and immunoblotting

Nuclear extracts were prepared and EMSAs were performed with 5 µg of cell extracts and ³²P-labeled double-stranded high affinity SIS-inducible element (hSIE) (m67) oligonucleotide, as previously described (27). STAT3 DNA binding was blocked using STAT3 Abs (28), as previously described (29). For immunoblotting, 10 µg of whole cell lysates was fractionated on 7.5% polyacrylamide gels using SDS-PAGE, and transferred to polyvinylidene fluoride membranes (Millipore, Bedford, MA). mAbs against STAT1 and STAT3 were obtained from BD Transduction Laboratories (Lexington, KY). Phosphorylation-specific STAT1 (Tyr⁷⁰¹) and STAT3 (Tyr⁷⁰³) Abs were purchased from Cell Signaling Technology (Beverly, MA).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Decreased anti-inflammatory activity of IL-10 in IFN--primed macrophages

A key suppressive activity of IL-10 is inhibition of cytokine production (10). We investigated the effects of IFN- priming on the ability of IL-10 to suppress LPS-induced TNF- production. Primary blood monocytes were cultured for 2 days with M-CSF with or without IFN-, and then stimulated with LPS in the presence or absence of IL-10. As expected, LPS-induced TNF- production in control macrophages was suppressed by IL-10 (Fig. 1). In IFN--primed macrophages, the effectiveness of IL-10 in suppressing TNF- production was diminished (Fig. 1). In independent experiments with macrophages derived from five different blood donors, the level of suppression of TNF- production by IL-10 was variable, but the reversal of IL-10 function by IFN- was consistent and reproducible. These results indicate that IFN--primed macrophages become refractory, at least in part, to the anti-inflammatory effects of IL-10.

View larger version (21K): [in this window] [in a new window]   FIGURE 1. IFN- impairs IL-10 anti-inflammatory activity. Human peripheral blood monocytes (>97% CD14+) were cultured for 2 days with M-CSF (10 ng/ml) with or without IFN- (250 pg/ml), treated with IL-10 for 12 h, and then activated with LPS (100 ng/ml). Supernatants were collected 18 h later, and TNF- levels were measured using ELISA. One representative experiment of five is shown; in all five experiments, IFN- blocked IL-10 suppression of TNF- production by >50%.

Gain of IL-10 proinflammatory function in IFN--primed macrophages

Type I IFNs were previously reported to enhance the activation of IFN--inducible genes by IL-6 (5). We analyzed the effect of IFN- priming on IL-10 induction of typical IFN--inducible, proinflammatory genes (30). Stimulation of control macrophages with IL-10 had no detectable effect on mRNA levels of IFN regulatory factor 1 (IRF-1), a transcription factor whose expression is induced by IFN- in a STAT1-dependent manner (31) (Fig. 2A). In contrast, IL-10 treatment strongly increased IRF-1 mRNA levels in IFN--primed macrophages (Fig. 2A). Because IRF-1 plays an important role in the activation of numerous IFN--inducible genes (31), this result suggested that IL-10 may induce expression of at least a subset of IFN--inducible genes in IFN--primed macrophages. We tested this hypothesis by determining the effects of IL-10 on the expression of the IFN--inducible chemokines, IFN--inducible protein-10 (IP-10; CXCL10) and monokine induced by IFN- (Mig) (CXCL9). Similar to IRF-1, IL-10 strongly activated expression of IP-10 and Mig in IFN--primed, but not in control, macrophages (Fig. 2, B and C). As a control for IL-10 stimulation, we examined the effects of IFN- priming on IL-10 induction of expression of suppressor of cytokine synthesis 3, which is not dependent on STAT1 (9). IL-10 induced comparable expression of suppressor of cytokine synthesis 3 in control and IFN--primed macrophages (Fig. 2D), demonstrating specificity in superinduction of only certain genes, and indicating that both control and IFN--primed macrophages had received an IL-10 signal. These results have been reproduced in six independent experiments. We tested the effects of IL-10 on IP-10 protein production. In a dose-response experiment, IP-10 protein production by control macrophages was not detected until a dose of 50 ng/ml IL-10 was used (Fig. 2E). IP-10 production was modest (<250 pg/ml) even at the highest concentrations of IL-10 (50 and 100 ng/ml). In contrast, in IFN--primed macrophages, 2 ng/ml IL-10 induced IP-10 protein production, and IP-10 production increased as the IL-10 concentration was increased (Fig. 2E). In IFN--primed macrophages, IL-10 induced up to 1000 pg/ml IP-10, whereas a saturating concentration of IFN-, a well-established strong inducer of IP-10, induced 1800 pg/ml IP-10 (Fig. 2E). Thus, IFN- priming enhanced IL-10 induction of IP-10 at the protein level, and IL-10 induced biologically significant levels of IP-10 similar to those induced by IFN-. Overall, the results demonstrate that IFN- priming confers a proinflammatory gain of function on IL-10. Our findings mirror in vivo results in human experimental endotoxemia, in which IL-10 induced IP-10 and Mig production only when given after, but not before, LPS administration (13, 14).

View larger version (23K): [in this window] [in a new window]   FIGURE 2. IL-10 induces expression of IFN--inducible, STAT1-dependent genes in IFN--primed macrophages. Control or IFN--primed monocyte-derived macrophages were stimulated with IL-10 for 30 min (A) or 3 h (B–D), and mRNA levels were measured using real-time PCR, as described (8 ). E, Control or IFN--primed macrophages were stimulated overnight with the indicated concentrations of IL-10 or IFN- (100 U/ml), and de novo production of IP-10 protein was measured using ELISA.

IFN- increases IL-10 activation of STAT1

Previous reports showed that low levels of IFN- enhance activation of STAT1 by IFN- or IL-6 (2, 4, 5, 8). We wished to test whether activation of IFN--inducible, STAT1-dependent genes by IL-10 in IFN--primed macrophages (Fig. 2) could be explained by IL-10 activation of STAT1. Macrophages were cultured for 2 days with M-CSF with or without IFN-, stimulated with IL-10 for 10 min, and immunoblotting was used to measure STAT tyrosine phosphorylation. IL-10 effectively induced tyrosine phosphorylation of STAT3 in control cells, and induced comparable levels of STAT3 tyrosine phosphorylation in IFN--primed macrophages (Fig. 3A, top panel). IL-10 did not induce detectable levels of STAT1 tyrosine phosphorylation in control macrophages, but strongly activated STAT1 tyrosine phosphorylation in IFN--primed macrophages (Fig. 3A, second panel). Increased STAT1 tyrosine phosphorylation was associated with increased STAT1 protein levels that were induced by IFN- (Fig. 3A, fourth panel; a replicate filter from the same experiment is shown). STAT3 levels were comparable in all lanes, confirming comparable loading of gels (third panel). Increased expression and activation of STAT1 by IL-10 in IFN--primed macrophages were reproducibly observed in >10 independent experiments using different blood donors (data not shown). In some experiments, IL-10 induced low, barely detectable levels of tyrosine-phosphorylated STAT1 in control macrophages, a phenomenon that we attribute to lymphocyte contamination of cultures and endogenous production of IFN. Signaling by all cytokines that use the Jak-STAT pathway was not nonspecifically sensitized, as there was no increase in STAT activation by GM-CSF or IL-4 in IFN--primed macrophages (data not shown).

View larger version (42K): [in this window] [in a new window]   FIGURE 3. IL-10 activates STAT1 in IFN--primed macrophages. Monocyte-derived macrophages primed for 2 days with IFN- (250 pg/ml) and control macrophages cultured in parallel without IFN- were stimulated with IL-10 (50 ng/ml) for 10 min. A, STAT activation was measured using immunoblotting of whole cell extracts to measure STAT tyrosine phosphorylation. B, EMSA with the hSIE oligonucleotide that binds STAT1 and STAT3. STAT3 Abs were added 15 min before adding radiolabeled probe, as previously described (28 29 ).

We wished to address whether STAT1 activation by IL-10 was causally related to the induction of IP-10 and Mig expression, and whether STAT1 contributed to the diminished IL-10 suppression of TNF- production observed in IFN--primed macrophages. Therefore, we compared the effects of IFN- on IL-10 function in bone marrow-derived macrophages from STAT1-deficient and genetically matched control mice in three independent experiments. Similar to human macrophages, IL-10 induced IP-10 and Mig mRNA expression only in IFN--primed wild-type murine macrophages (Fig. 4A). In contrast, IL-10 did not induce expression of IP-10 or Mig mRNA in IFN--primed STAT1-deficient murine macrophages (Fig. 4A). These results indicate that IL-10 activation of IP-10 and Mig expression in IFN--primed macrophages is dependent upon activation of STAT1 in these cells. When regulation of LPS-induced TNF- production was examined, IL-10 suppressed TNF- production effectively in unprimed wild-type and STAT1-deficient macrophages (Fig. 4B). IL-10 suppression of TNF- production was diminished in both wild-type and STAT1-deficient macrophages that had been pretreated with IFN- (Fig. 4B). Thus, the suppressive effect of IFN- priming on IL-10 inhibition of TNF- production was not dependent on STAT1.

View larger version (20K): [in this window] [in a new window]   FIGURE 4. Role of STAT1 in mediating IL-10 function in IFN--primed macrophages. STAT1-deficient and genetically matched wild-type bone marrow-derived macrophages were cultured in the presence or absence of IFN- for 2 days and then stimulated with IL-10. A representative experiment of three is shown. A, Cells were stimulated for 3 h with IL-10 (100 ng/ml), and mRNA levels were measured using real-time PCR and normalized relative to GAPDH expression. B, Cells were cultured with 850 pg/ml (low dose) or 7.5 ng/ml (high dose) IFN- for 2 days. The indicated concentration of IL-10 was added for the final 16 h of culture, cells were stimulated with LPS (100 ng/ml) for 4 h, and TNF- levels in culture supernatants were measured using ELISA.

Protein kinase C (PKC) and protein tyrosine phosphatases (PTPs) suppress activation of STAT1 by IL-10

We previously found that activation of PKC by FcR ligation inhibits IL-10 signaling (26). Macrophages contain basal levels of PKC activity (26), and we used macrophages from PKC-deficient mice (32) to determine whether basal PKC activity played a role in suppressing STAT1 activation by IL-10 in control macrophages. In bone marrow-derived macrophages from control C57BL/6 or control PKC-deficient mice (33), IL-10 activated tyrosine phosphorylation of STAT3, but not STAT1 (Fig. 5A). In contrast, IL-10 activated both STAT3 and STAT1 tyrosine phosphorylation in PKC-deficient mice (Fig. 5A). These results indicate that PKC plays a role in suppressing IL-10 activation of STAT1 in control macrophages. This result is consistent with the autoimmune phenotype of PKC-deficient mice (32).

View larger version (25K): [in this window] [in a new window]   FIGURE 5. PKC and PTPs suppress activation of STAT1 by IL-10. A, Bone marrow-derived macrophages from wild-type, PKC-deficient, and PKC-deficient mice were stimulated for 10 min with IL-10 (50 ng/ml), and STAT activation was assessed using immunoblotting. B, Human control macrophages were pretreated for 10 min with 5 mM sodium orthovanadate before stimulation with IL-10. C, Bone marrow-derived macrophages from SHP-1 mutant (motheaten) mice were stimulated with IL-10, and STAT activation was measured using immunoblotting. D, Cell extracts from control macrophages or macrophages cultured for 2 days with 250 pg/ml or 7.5 ng/ml IFN- were analyzed using immunoblotting.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Although IL-10 is predominantly an anti-inflammatory cytokine, IL-10 can promote activation of certain cell types and can acquire proinflammatory activities in settings in which the immune system is active, such as endotoxemia, SLE, and after tissue transplantation (13, 14, 15, 16). Our results demonstrate that this balance between pro- and anti-inflammatory activities of IL-10 is regulated by type I IFNs. Type I IFNs are produced early during an innate immune response, and would thus ensure that IL-10 produced at these early time points does not inappropriately suppress immunity. Indeed, in a setting in which type I IFNs are expressed, IL-10 can actually contribute to immunity and inflammation (14). This system for modulating IL-10 activity may become dysregulated in chronic autoimmune or inflammatory diseases, such as SLE, that are characterized by high levels of type I IFNs. This notion is consistent with the proinflammatory activity of IL-10 that has been noted in SLE (16, 17). Indeed, IL-10 is a pathogenic factor in SLE, and neutralization of IL-10 results in attenuation of SLE in human patients and in animal models (36, 37).

Increased IL-10 activation of STAT1 provides a mechanism by which IFN- pretreatment of macrophages enhances IL-10 induction of proinflammatory gene expression. However, increased STAT1 activation cannot explain all aspects of altered IL-10 function in IFN--primed cells, as IL-10 inhibition of TNF- production was comparably diminished in wild-type and STAT1-deficient macrophages. Coupling of IL-10 to STAT1 activation differs from previously described IFN- priming of enhanced STAT1 activation by IFN- and IL-6 receptors because these cytokines induce substantial levels of activated STAT1 in control nonprimed cells. In contrast, IL-10 activation of STAT1 in control macrophages is low and is under tonic suppression by PKC. In addition, SHP-1 and other PTPs may play a role in suppressing IL-10 activation of STAT1 (Fig. 5). However, the phenotype of the motheaten mouse is complex, and it is possible that the effects of SHP-1 deficiency that were observed were indirect, even when purified in vitro differentiated cells were used. The mechanism by which SHP-1 regulates IL-10 signaling will be further addressed in future experiments. Interestingly, PKCs, including PKC, regulate the function of SHP-1 (38), and it is possible that IFN- priming works by inactivating SHP-1 directly, indirectly through regulation of PKC, or by alternative mechanisms.

	Acknowledgments

 
We thank Wai Ping Li for technical assistance, Xiaoyu Hu and Kyung-Hyun Park-Min for reviewing the manuscript, and Jim Darnell for providing STAT3 Abs.

	Footnotes

 
¹ This work was supported by grants from the National Institutes of Health and Kirkland Center for SLE Research (to L.B.I.).

² Address correspondence and reprint requests to Dr. Lionel B. Ivashkiv, Department of Medicine, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail address: ivashkivl{at}hss.edu

³ Abbreviations used in this paper: Jak, Janus kinase; hSIE, high affinity SIS-inducible element; IP-10, IFN--inducible protein-10; IRF-1, IFN regulatory factor 1; Mig, monokine induced by IFN-; PKC, protein kinase C; PTP, protein tyrosine phosphatase; SHP, Src homology 2 domain-containing phosphatase 1; SLE, systemic lupus erythematosus; IFNAR1, IFN- receptor 1.

Received for publication September 26, 2003. Accepted for publication March 10, 2004.

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