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Originally published online as doi:10.1189/jlb.0905493 on February 3, 2006

Published online before print February 3, 2006
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(Journal of Leukocyte Biology. 2006;79:797-802.)
© 2006 by Society for Leukocyte Biology

Regulation of PTX3, a key component of humoral innate immunity in human dendritic cells: stimulation by IL-10 and inhibition by IFN-{gamma}

Andrea Doni*, Mosca Michela{dagger}, Barbara Bottazzi*, Giuseppe Peri*, Sonia Valentino*, Nadia Polentarutti*, Cecilia Garlanda* and Alberto Mantovani*,{ddagger},1

* Istituto Clinico Humanitas (ICH), Rozzano, Milan, Italy;
{dagger} Department of Experimental Medicine and Public Health, University of Camerino, Macerata, Italy; and
{ddagger} Institute of General Pathology, University of Milan, Italy

1Correspondence: Istituto Clinico Humanitas (ICH), via Manzoni, 56 20089 Rozzano, Milan, Italy. E-mail: alberto.mantovani{at}humanitas.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The protopypic long pentraxin 3 (PTX3) is a unique, humoral pattern-recognition receptor, which plays a nonredundant function in innate resistance to pathogens. Dendritic cells (DC) of myelomonocytic origin, but not plasmacytoid DC, are a major source of PTX3 in response to Toll-like receptor (TLR) engagment. The present study was designed to explore the regulation of PTX3 production in DC. PTX3 production was induced by TLR ligands, CD40 ligand, and interleukin (IL)-1ß and was suppressed by dexamethasone, 1{alpha}, 25-dihydroxivitamin D3, and prostaglandin E2. It was unexpected that lipopolysaccharide (LPS)-stimulated PTX3 production was enhanced by IL-10 and inhibited by IL-4 and interferon-{gamma} (IFN-{gamma}). Enhancement of PTX3 production by IL-10 was also evident when Pam3 Cys-Ser-(Lys)4.3HCl, a TLR2-TLR1 agonist, polyionisicpolycytidylic acid, a TLR3 agonist, and IL-1ß were used as stimuli. The effect of IL-10 was blocked by an anti-IL-10 monoclonal antibody (mAb) or an anti-IL-10 receptor {alpha} mAb, which also reduced the LPS-induced production. Thus, production of PTX3 in DC is subjected to a distinct regulatory network, with inhibition by IFN-{gamma} and enhancement by IL-10. The amplification by IL-10 of production of a nonredundant component of fluid-phase innate immunity mirrors the IL-10 stimulatory function on B cells in adaptive immunity. As PTX3 is also an extracellular matrix component, IL-10-enhanced PTX3 production may play a role in orchestration of tissue remodeling in chronic inflammation.

Key Words: pentraxins • cytokines • tissue remodeling


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pentraxins are a superfamily of proteins usually characterized by a pentameric structure and highly conserved during evolution [1 2 3 ]. The classic short pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP), are acute-phase proteins in man and mouse, respectively. They are produced in the liver in response to inflammatory signals, most prominently interleukin (IL)-6. CRP and SAP bind, in a calcium-dependent manner, different ligands, and they are involved in the innate resistance to microbes and the scavenging of cellular debris and extracellular matrix (ECM) components [4 ].

The prototypic, long pentraxin 3 (PTX3) shares similarities with the classical, short pentraxins; however, it has an unrelated, long N-terminal domain coupled to the C-terminal pentraxin domain and differs in gene organization, cellular source, and ligands recognized [3 ]. PTX3 is produced rapidly and released by several cell types, in particular, by mononuclear phagocytes, dendritic cells (DC), fibroblasts, and endothelial cells [3 , 5 6 7 ], in response to primary inflammatory signals [e.g., Toll-like receptor (TLR) engagment, tumor necrosis factor {alpha}, IL-1ß]. PTX3 binds with high affinity the complement component C1q, the ECM component TSG6, and selected mocroorganisms, including Aspergillus fumigatus and Pseudomonas aeruginosa [8 9 10 11 12 ]. PTX3 activates the classical pathway of complement activation and facilitates pathogen recognition by macrophages and DC [3 , 9 , 12 ].

Recent studies in gene-modified mice have shown that PTX3 plays complex, nonredundant functions in vivo, ranging from the assembly of a hyaluronic acid-rich ECM and female fertility to innate immunity against diverse microorganisms [3 , 9 , 11 12 13 14 15 ].

Outer membrane protein A (OmpA) is an essential component of the outer membrane of enterobateriaceae and is recognized by PTX3, which acts as a nonredundant, humoral amplification loop of the innate response to OmpA, behaving as a bona fide ante-antibody [16 ].

Diverse cell types can produce PTX3 in response to inflammatory signals [3 ], but DC are a major source of this ante-antibody [6 ]. DC are key regulators of innate immunity and of the initiation of the adaptive immune response [17 ]. It is interesting that PTX3 production is restricted to DC of myelomonocytic lineage, whereas plasmacytoid DC are unable to produce PTX3 when exposed to appropiate signals [6 ]. Given the role of PTX3 in humoral innate immunity and its copious production by DC, it was important to define its regulation by extracellular signals. Here, we report that PTX3 production by DC shows a unique pattern of regulation by cytokines and inflammatory mediators with enhancement by IL-10 and inhibition by interferon-{gamma} (IFN-{gamma}).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell culture media and reagents
The following reagents were used for tissue culture: pyrogen-free saline (S. A. L., Bergamo, Italy), RPMI-1640 medium (Biochrom, Berlin, Germany), 200 mM L-glutamine (Biochrom), and aseptically collected fetal calf serum (FCS; Hyclone Laboratories, Logan, UT). Human recombinant granulocyte macrophage-colony stimulation factor (hrGM-CSF) was a gift from Novartis (Milan, Italy), and human IL-13 was a gift from Dr. Adrian Minty (Sanofi Elf Bio Recherches, Labège, France). hrIFN-{gamma}, IFN-ß, and IL-4 were purchased by Peprotech (London, UK), and hrIL-10 was kindly provided by Professor Giorgio Trinchieri (Schering Plough, Kenilworth, NJ). IFN-{alpha} (Roferon-A) was for clinical use from Roche (Nutley, NJ). Dexamethasone (Dex)-21-phosphate disodium salt was purchased by MP Biomedicals (Germany). 1{alpha}, 25-Dihydroxivitamin D3 (VitD3) was a gift from Prof. Luciano Adorini (Bioxell, Milan, Italy).

Prostaglandin E2(PGE2) was obtained from Sigma-Aldrich (St. Louis, MO). Stimultation by CD 40 ligand (CD40L) was performed by CD40 cross-linking, and DC were cocultured with CD40L-transfected J558 cell line at a 4:1 ratio [18 ]. The following TLR agonists were used to activate myeloid DC: Lipopolysaccharide (LPS) from Escherichia coli strain 055:B5 was obtained from Sigma-Aldrich, and LPS from E. coli serotype R515 (>99.9% of purity) was obtained from Alexis (San Diego, CA); polyionisicpolycytidylic acid (Poly I:C) was purchased from Amersham Pharmacia Biotech (Little Chalfont, UK); the bioactive peptide Pam3 Cys-Ser-(Lys)4 .3HCl (Pam3 Cys) was from Alexis.

To neutralize endogenous IL-10 function, a mouse monoclonal antibody (mAb), immunoglobulin G1 (IgG1) Clone 37607, anti-human IL-10 receptor {alpha} (IL-10R{alpha}), and a mouse mAb (IgG2B Clone 23738) anti-human IL-10 were used (R&D Systems, Abingdon, UK). A neutralizing anti-CD64 mouse mAb (IgG1) was used as an irrelevant control (Serotech, Oxford, UK).

DC
Monocyte-derived DC were generated as described previously [19 ]. Briefly, blood monocytes were obtained from fresh buffy coats of healthy donors (courtesy of the Centro Trasfusionale, Ospedale Niguarda, Milan, Italy) by Ficoll (Biochrom) and Percoll (Amersham, Uppsala, Sweden) and after discard of nonadherent cells. Purified monocytes were cultured for 6 days at 1 x 106 cells/ml in six-well tissue-culture plates (BD Biosciences, San Jose, CA) in RPMI-1640 medium supplemented with 2 mM L-glutamine and 10% FCS, 50 ng/ml GM-CSF, and 20 ng/ml IL-13. Monocyte-derived DC were then cultured for the reported periods in RPMI-1640 medium supplemented with 2 mM L-glutamine and 2% FCS at 1 x 106 cells/ml/0.4 ml in 48-well tissue-culture plates (BD Biosciences) in the presence of different proinflammatory stimuli: LPS, 0.1–1–10 ng/ml; Pam3 Cys, 0.05–0.5–5 µg/ml; Poly I:C, 0.1–1–10 µg/ml. The anti-IL-10 (5 µg/ml) and anti-IL-10R{alpha} (5 µg/ml) mAb were added 1 h prior to the treatment of the above-indicated stimuli and cytokines. Myeloid DC were incubated with IL-10 and IFN-{gamma} 1 h before to challenge with proinflammatory stimuli. Supernatants were collected, and PTX3 concentrations were measured by enzyme-linked immunosorbent assay (ELISA).

PTX3 protein and transcripts
Protein levels of PTX3 were detected using an ELISA assay described previously [20 ].

For Northern blot analysis, total RNA was extracted by the TRIzol method, according to the manufacturer’s instructions (Invitrogen, Life Technologies, Carlsbad, CA), blotted, and hybridized as described [6 ]. mRNA densitometric analysis was performed by quantification of relative optical density x area using Image analysis software (Image Research, Inc., Ontario, Canada).

Statistical analysis
Statistical analysis was performed by using the Student’s t-test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In a first series of experiments, we examined an entire range of molecules capable of affecting DC function for their capacity to regulate PTX3 production, alone or in concert with LPS. Figure 1A shows a typical experiment with LPS, IL-10, and IFN-{gamma} and combinations thereof; Figure 1B summarizes results of a series of 32 experiments.


Figure 1
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  		Figure 1. Effect of different modulators of DC function on PTX3 production: divergent effects by IL-10 and IFN-{gamma}. (A) A representative experiment with LPS, IL-10, and IFN-{gamma} and combinations thereof. Results refer to mean ± SD of a triplicate. *, P < 0.05, versus LPS. **, P < 0.01, versus unstimulated. (B) Summarized results of a series of 32 experiments as percentage of the LPS response used as reference. The number of experiments performed was 19 (IL-10) and 17 (IFN-{gamma}). *, P < 0.05, versus LPS.

 
As shown in Figure 1B , IL-4/IL-13, IFN-{gamma}, IFN-{alpha}, IFN-ß, VitD3, PGE2, and Dex did not induce PTX3 production. In contrast, CD40L was an inducer of PTX3 and resulted in release of 2.41 ± 0.73 ng/ml, corresponding to 5.9 ± 1.78% of the response to LPS.

It was unexpected that in 11 out of 19 experiments performed, IL-10 caused low but detectable levels of PTX3 production by DC (256±94 pg/ml) corresponding to 0.71 ± 0.26% of the response to LPS.

The LPS-induced production of PTX3 in DC was inhibited by IL-4 (33.2±13.25%), VitD3 (51.6±3.4%), Dex (59.6±14.0%), and PGE2 (74.3±10.1%). Conversely, CD40L strongly amplified the LPS-induced production of LPS (80.1±15.7%). IFN-{alpha} and IFN-ß had no suppressive activity; rather, they amplified PTX3 production in response to LPS (44.0±17.5% and 40.59±17.3%, respectively; Fig. 1B ).

When IL-10 was combined to LPS, enhancement of PTX3 production was observed consistently. In a series of 19 experiments, IL-10 (20 ng/ml) caused a 69 ± 11.58% augmentation of PTX3 released by DC exposed to 10 ng/ml LPS.

In contrast, IFN-{gamma} and IL-4 inhibited LPS-induced PTX3 production. In a series of 19 experiments, IFN-{gamma} caused a 38.3 ± 15.5% reduction of the LPS response (Fig. 1B) .

The divergent effects of IL-10 and IFN-{gamma} were dose-related (range of 0.2–20 ng/ml for IL-10 and 2.5–250 ng/ml for IFN-{gamma}). Similarly, inhibition (IFN-{gamma}) or enhancement (IL-10) of the response to LPS was observed at LPS concentrations ranging from 0.1 to 10 ng/ml (Fig. 2A and2B ). Results presented in Figures 1 and 2 were obtained after 24 h of culture. Enhancement by IL-10 was also observed at time-points ranging from 8 h to 48 h (data not shown). DC numbers were not affected by IL-10 under these conditions (data not shown).


Figure 2
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  		Figure 2. The divergent effects of IL-10 (A) and IFN-{gamma} (B). Different concentrations of LPS, IL-10, and IFN-{gamma} were used. Results are mean ± SE of five to six different experiments. *, P < 0.02, versus LPS.

 
When transcript levels were assessed by Northern analysis, IL-10 was found to cause weak induction of PTX3 mRNA and to up-regulate LPS induction (Fig. 3 ). Densitometric analysis revealed that a combined treatment of IL-10 (20 ng/ml) with 1 ng/ml or 10 ng/ml LPS caused an increase in transcript levels corresponding to 119% and 89% of the response to LPS, respectively. In contrast, a combined treatment of IFN-{gamma} markedly inhibited LPS-induced PTX3 expression in DC, with a 37% and 48% reduction of the response to 1 ng/ml and 10 ng/ml LPS, respectively. Similarly, IL-4 inhibited the LPS-elicited PTX3 mRNA expression in DC (Fig. 3) .


Figure 3
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  		Figure 3. Regulation of LPS-induced PTX3 mRNA by IL-10 and IFN-{gamma}: The bottom part is the ß-actin hybridization.

 
It was of interest to assess whether the enhancement of PTX3 by IL-10 in DC was also observed using agonists, which activate other members of the TLR and IL-1R family. IL-10 (20 ng/ml) caused an increase in the response of DC to Pam3 Cys (TLR2-TLR1 agonist, 0.05–5 µg/ml), ranging from 1.2- to 4.85-fold, and an increase in the response to Poly I:C (TLR3 agonist used at 0.1, 1, and 10 µg/ml), ranging from 1.6- to 2.9-fold (Fig. 4 ). IL-1ß is a weak inducer of PTX3 in DC. As shown in Figure 4 , IL-10 drammatically increased the IL-1ß-induced PTX3 production from 1.77 ± 0.36 ng/ml to 9.94 ± 1.67 ng/ml (n=6, P<0.01).


Figure 4
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  		Figure 4. Enhancement by IL-10 of PTX3 production induced by TLR agonists or IL-1ß. Results are mean ± SE of five (Pam3 Cys), nine [Poly I:C (poli I:C)], and five (IL-1ß) experiments, respectively. *, P < 0.05, versus Pam3 Cys, Poly I:C, and IL-1ß.

 
LPS induces IL-10 production in myelomonocytic cells and DC [21 ]. It was therefore important to evaluate whether endogenous IL-10 contributes to the PTX3 induction by LPS. As shown in Figure 5 , neutralizing anti-IL-10 (5 µg/ml) or anti-IL-10R{alpha} (5 µg/ml) mAb caused a modest (24.5±7.3%, P<0.05, and 41.13±8.58%, P<0.02, respectively) but significant decrease in the release of PTX3 in LPS-stimulated DC. These same reagents also blocked the enhancement of the LPS response by exogenous IL-10 (Fig. 5) . These results suggest that endogenous production of IL-10 contributes to the LPS-elicited PTX3 production.


Figure 5
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  		Figure 5. Effect of endogenous IL-10 on PTX3 production by DC. Results represent mean ± SE of six experiments. DC were cultured with LPS, with or without IL-10, in the presence of anti-IL-10 or IL-10R{alpha} mAb. An irrelevant control mAb did not affect the production (not shown). *, P < 0.02, versus LPS; **, P < 0.01, versus LPS + IL-10.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The long pentraxin PTX3 is a fluid-phase pattern recognition receptor, which plays a nonredundant role in resistance against selected pathogens [3 , 9 , 16 ]. Myeloid, but not plasmacytoid, DC are major producers of PTX3 in response to TLR engagment [6 ]. The present study was designed to characterize the regulation of PTX3 production in DC. CD40L was a weak inducer of PTX3 but markedly amplified LPS-elicited PTX3. IFN-{gamma} and IL-4 did not induce PTX3 production and significantly reduced the induction by LPS. PTX3 production was also inhibited by Dex, VitD3, and PGE2 (Fig. 1B) . In contrast, IL-10 had weak and inconsistent stimulatory activity alone but significantly amplified the LPS-induced production. Enhancement of PTX3 by IL-10 was also observed when Pam3 Cys (a TLR2-TLR1 agonist), Poly I:C (a TLR3 agonist), and IL-1ß were used. IL-1ß was a weak stimulus for PTX3 production in DC, but its action was amplified drammatically by IL-10 (Fig. 4) . Thus, PTX3 production in DC is subjected to a distinct, regulatory network, characterized, in particular, by opposing effects of IFN-{gamma} (inhibitory) and IL-10 (stimulatory).

The finding that IFN-{gamma} inhibits LPS-induced PTX3 production in DC is consistent with a previous study of transcript expression in myelomonocytic cells and endothelial cells [22 , 23 ]. IFN-{gamma} and LPS are generally synergistic [24 ], and a limited set of LPS-induced molecules is inhibited by IFN-{gamma}. These include, for instance, the expression of macrophage-inflammatory protein (MIP)-1{alpha}, MIP-1ß, MIP-2, and keratinocyte-derived chemokine [25 ].

Conversely, IFN-{alpha} and IFN-ß, in inflammatory conditions, enhance the production of PTX3 in myeloid DC (Fig. 1B) . Type I and type II IFNs use distinct cell-surface receptors and regulate gene expression by Janus tyrosine kianse–signal transducer and activator of transcription signaling [26 ]. The gene expression profiles activated by type I and type II IFNs are considerably different [27 28 29 ]. It is therefore hardly surprising that type I and type II IFNs have divergent effects on PTX3 production.

IL-10 is a weak and inconsistent stimulus of PTX3 production but consistently enhances its expression and release in response to TLR agonists and IL-1ß. In a whole genome-profiling effort, induction of PTX3 transcripts by IL-10 and enhancement by IL-10 and LPS were observed [30 ]. The present study confirms these previous gene-profiling data and demonstrates actual protein production.

PTX3 has properties similar to antibodies [3 , 16 ]; its production is induced by pathogen recognition, and it recognizes microbial moieties, activates complement, and facilitates recognition by phagocytes [3 , 9 , 16 ]. Thus, this long pentraxin behaves as a bona fide ante-antibody. In this perspective, it is interesting that IL-10 stimulates B cell differentiation and antibody production [31 ]. Thus, IL-10 stimulates the humoral arm of innate (PTX3) and adaptive (antibodies) immunity.

PTX3 is a constituent of the ECM [3 , 11 ]. It plays a nonredundant role in the assembly of the hyaluronan-rich viscoelastic matrix of the cumulus oophorus and hence, in female fertility [3 , 11 , 13 ]. PTX3 binds TSG6, a hyaluronic acid-binding protein, and may act as a focal point of the assembly of hyaluronic acid-rich matrices [3 , 11 ]. IL-10 is involved in the chronic and resolution phase of inflammation [31 ]. Transcriptional profiling analysis revealed that IL-10 induces a set of genes (e.g., type I collagen, fibronectin, versican, {alpha}1-antitrypsin) related to tissue remodeling [30 , 32 33 34 ]. Here, we report that IL-10 enhances PTX3 in DC and fibroblasts (data not shown). PTX3 enhancement by IL-10 is likely to play a role in tissue remodeling in chronic inflammation.


   ACKNOWLEDGEMENTS
 
This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero Istruzione Università e Ricerca (MIUR), Centro Nazionale delle Richerche (CNR), and European Commission. A. D. and M. M. contributed equally to this work.

Received September 2, 2005; revised October 21, 2005; accepted November 21, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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