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Proc Natl Acad Sci U S A. Mar 4, 2008; 105(9): 3515–3520.
Published online Feb 22, 2008. doi:  10.1073/pnas.0712381105
PMCID: PMC2265135
Immunology

Interleukin-32 induces the differentiation of monocytes into macrophage-like cells

Abstract

After emigration from the bone marrow to the peripheral blood, monocytes enter tissues and differentiate into macrophages, the prototype scavenger of the immune system. By ingesting and killing microorganisms and removing cellular debris, macrophages also process antigens as a first step in mounting a specific immune response. IL-32 is a cytokine inducing proinflammatory cytokines and chemokines via p38-MAPK and NF-κB. In the present study, we demonstrate that IL-32 induces differentiation of human blood monocytes as well as THP-1 leukemic cells into macrophage-like cells with functional phagocytic activity for live bacteria. Muramyl dipepide (MDP), the ligand for the intracellular nuclear oligomerization domain (NOD) 2 receptor, has no effect on differentiation alone but augments the monocyte-to-macrophage differentiation by IL-32. Unexpectedly, IL-32 reversed GM-CSF/IL-4-induced dendritic cell differentiation to macrophage-like cells. Whereas the induction of TNFα, IL-1β, and IL-6 by IL-32 is mediated by p38-MAPK, IL-32-induced monocyte-to-macrophage differentiation is mediated through nonapoptotic, caspase-3-dependent mechanisms. Thus, IL-32 not only contributes to host responses through the induction of proinflammatory cytokines but also directly affects specific immunity by differentiating monocytes into macrophage-like cells.

Keywords: immune cell differentiation, inflammation, muramyl dipeptide, cytokine, antigen presentation

In addition to their role for the activation of the antimicrobial function of leukocytes, cytokines have an important role for the proliferation and differentiation of myeloid cell populations. IL-32 is a proinflammatory cytokine that is induced by IL-18 and IFN-γ in human epithelial cells (1). The gene expression of IL-32 is increased in human T lymphocytes and natural killer cells when stimulated by mitogens or IL-2 (2, 3). In turn, IL-32 also induces the synthesis of proinflammatory cytokines such as IL-1β, IL-6, and TNFα. Elevated levels of mRNA have been reported in synovial tissue explants from patients with rheumatoid arthritis, but not osteoarthritis (4). The intensity and frequency of tissue-staining levels of IL-32 protein in synovial cells of patients with rheumatoid arthritis correlate with disease activity, as well as tissue levels of TNFα, IL-1β, and IL-18 (5). Affected tissues from patients with Crohn's disease and ulcerative colitis show prominent staining for IL-32 (6, 7). IL-32 is produced by peripheral blood mononuclear cells (PBMCs) stimulated with Mycobacterium tuberculosis (8), and IL-32 acts synergistically with muramyl peptide (MDP) to induce IL-6 via caspase-1-dependent IL-1β (6).

In vitro, cytokines such as macrophage colony-stimulating factor (M-CSF) induce differentiation of monocytes into macrophages (9), whereas a combination of GM-CSF and IL-4 induces differentiation into dendritic cells (DCs) (1013). Cytokines such as IL-6 and IFN-γ can modulate GM-CSF/IL-4-induced monocyte differentiation by switching from DCs to macrophages (10, 14). Although IL-6 induces this effect through the up-regulation of M-CSF receptors on the monocytes (14), it is unclear how IFN-γ exerts its effect on monocyte differentiation.

Because IFN-γ is a particularly potent inducer of IL-32 expression (1), we hypothesized that IL-32 can modulate the differentiation of monocytes in addition to its stimulatory effects on cytokine induction. Indeed, we observed that IL-32 induces differentiation of monocytes into macrophage-like cells, but the effect of IL-32 on monocyte differentiation was unexpectedly mediated through a caspase-3-dependent mechanism. In addition to this effect, IL-32 can switch the GM-CSF/IL-4-induced DC differentiation toward a macrophage-like cell. This latter property suggests that IL-32 may function in host defense against obligate intracellular microorganisms such as M. tuberculosis.

Results

IL-32 Alters the Morphology of Monocytic Cells.

In the course of studying the induction of cytokines by recombinant IL-32γ, we noted morphological changes that were not observed in control cultures. Therefore, we specifically examined the THP-1 monocytic cell line in the presence of the cytokine. When THP-1 cells were treated for 3 days with IL-32γ, significant differences were observed in their morphology. As shown in Fig. 1A2, the cells were flattened with extensive pseudopodia compared with control cells (Fig. 1A1). For comparison, high concentrations of LPS (10 μg/ml) had no effect (Fig. 1A3). Similar morphological changes were apparent in a dose–response study of 3-day exposure to IL-32γ in freshly isolated PBMCs from healthy human subjects (Fig. 1B).

Fig. 1.
IL-32γ-induced human monocytic THP-1 or PBMC differentiation. (A) THP-1 cells were treated with 30 ng/ml recombinant IL-32γ (A2), 10 μg/ml LPS (A3), or control (A1) for 48 h in the absence of FCS. (B) PBMCs were stimulated with ...

We also studied the effect of IL-32α on THP-1 cell differentiation. In several experiments, IL-32α consistently required higher concentrations (20- to 50-fold) than IL-32γ for inducing similar morphological changes (data not shown). Moreover, because of our previous findings that IL-32γ synergized with MDP for cytokine induction (6), we examined the effect of costimulation of IL-32 with MDP. Using a concentration of 1 μg/ml MDP, there were no morphological changes on THP-1 or PBMCs after 3 days of incubation. However, both IL-32α and IL-32γ effects on morphology were clearly enhanced by the presence of MDP (data not shown).

Cell-Surface Markers of DCs and Macrophages.

As shown in Fig. 1C, IL-32γ-treated cells appeared differentiated into either macrophages or DCs. Therefore, we performed detailed analyses of macrophage and DC markers. As shown in Fig. 2A, IL-32γ induced the transcription of both CD1a and CD14 mRNA in human monocytes. In contrast, the expression of CD64 was slightly decreased. We next determined whether IL-32γ-treated PBMC cell-surface markers exhibit changes similar to those observed for steady-state mRNA levels. As shown in Fig. 2B, the changes in mRNA levels by IL-32γ were accompanied by similar changes in the cell-surface markers. CD14 expression was increased, and there also were small increases in CD1a and CD83 expression, whereas IL-32γ decreased CD64 expression (Fig. 2B).

Fig. 2.
Surface markers in PBMCs after IL-32γ-induced macrophage differentiation. (A) RT-PCR of the macrophage and DC cell markers CD1a, CD14, and CD64 after stimulation of PBMCs with 30 ng/ml IL-32γ and 10 μg/ml LPS at the indicated time ...

We next determined whether IL-32-differentiated cells exhibited phagocytosis, a functional property characteristic of macrophages. After 3 days of IL-32γ-induced differentiation, THP-1 cells were incubated for 6 h with transformed Escherichia coli. As shown in Fig. 2C, THP-1 cells that had been differentiated into macrophage-like cells in the presence of IL-32γ exhibited active phagocytic properties. These data support the concept that differentiation induced by IL-32 leads to a cell population that actively displays the function of an effective phagocyte, a property uniquely characteristic for macrophages rather than DCs.

To observe the consistency of the IL-32γ effect on surface markers of the macrophage phenotype, PBMCs from seven healthy donors were incubated with IL-32γ for 3 days, and the expression of CD14, CD1a, CD64, and CD83 was analyzed by FACS. As shown in Fig. 3, IL-32γ induced a consistent increase in the expression of both CD1a and CD14, which was significant (P < 0.05), compared with control cells incubated with medium only. In contrast, no significant effect was observed on the expression of CD64 and CD83 (Fig. 3).

Fig. 3.
IL-32-induced macrophage differentiation markers of human PBMCs. PBMCs were incubated with culture medium (RPMI medium 1640) or 30 ng/ml IL-32γ at 37°C. FACS analysis of the expression of the macrophage and DC markers CD14, CD1a, CD64, ...

IL-32 Influences GM-CSF- or GM-CSF/IL-4-Induced DC Differentiation.

Human PBMCs were stimulated with GM-CSF in the presence or absence of IL-32γ. After 3 days, the expression of cell-surface markers was assessed. IL-32γ antagonized GM-CSF-induced DC markers, especially CD1a, whereas the percentage of cells positive for the expression of the macrophage marker CD14 was increased (Fig. 4A). In additional experiments, we examined the effects of IL-32γ on the GM-CSF/IL-4-induced differentiation of monocytes into DCs. The combination of GM-CSF/IL-4 prominently increased the cell-surface markers of DCs compared with GM-CSF alone. The GM-CSF/IL-4-induced DC differentiation was reversed by the addition of IL-32γ to the cell culture (Fig. 4B).

Fig. 4.
The effect of IL-32 on DC differentiation. GM-CSF-induced or a combination of GM-CSF/IL-4-induced DC markers after incubation with IL-32γ. (A) FACS analysis of the macrophage and DC markers CD14, CD1a, CD64, and CD83 in human PBMCs stimulated ...

Caspase-3-Dependent Cell Differentiation.

IL-32 activates several intracellular signaling pathways (1). The p38-MAPK and NF-κB pathways induce the production of proinflammatory cytokines, whereas the activation of proinflammatory caspases, such as caspase-1, is responsible for its synergistic effects on signaling induced by the intracellular pattern-recognition receptors nuclear oligomerization domain 1 (NOD1) and NOD2 (6). By blocking the p38-MAPK pathway with a specific inhibitor, we observed that TNFα, IL-1β, and IL-6 production induced by IL-32γ was nearly entirely dependent on this pathway (Fig. 5A). In contrast, a broad pan-caspase inhibitor (z-VAD-fmk) reduced only the secretion of IL-1β, but not of TNFα or IL-6 (Fig. 5B). The effect of the pan-caspase inhibitor was most likely due to a reduction in the posttranslational activation of caspase-1. However, the pan-caspase inhibitor completely blocked IL-32-induced differentiation (Fig. 5C), whereas the p38-MAPK inhibitor had no effect (data not shown). In addition, the inhibitory effects of the pan-caspase inhibitor were specific for macrophage differentiation because the DC differentiation induced by GM-CSF/IL-4 was not affected by caspase inhibition (data not shown).

Fig. 5.
The effect of caspase inhibition on IL-32γ-induced differentiation. (A) The effect of the p38MAPK inhibitor (2 μM SB203580) on 30 ng/ml IL-32γ induced the release of TNFα, IL-1β, and IL-6 from PBMCs. (B) The effect ...

We performed additional experiments to identify which member of the caspase family was responsible for inhibiting the effect of IL-32γ. As shown in Fig. 5D, we observed that a specific caspase-3 inhibitor (z-DEVD-fmk) (15) displayed the same inhibitory effects on IL-32γ-induced macrophage differentiation as did the pan-caspase inhibitor. In contrast, specific inhibitors of caspase-1, -8, or -9 had no effects on cell differentiation induced by IL-32γ (Fig. 5D). The effects on the differentiation of PBMCs were confirmed by similarly incubating with medium alone (Fig. 5E1), IL-32γ (Fig. 5E2), or IL-32γ and the caspase inhibitor, z-VAD-fmk (Fig. 5E3). In a dose range of the caspase-1 inhibitor (0.1, 0.5, 1.0, 5, and 10 μM), there was a 25% reduction in IL-1β secretion at 5 μM and a 90% reduction at 10 μM. Lower concentrations had no effect. Other caspase inhibitors, which had no effect at 10 μM, were tested at 10, 20, and 50 μM. Lower concentrations of the caspase-3 inhibitor (0.1, 0.5, and 1.0 μM) also were without effect. However, 5 μM reduced CD14 expression to the same level as 10 μM (data not shown).

Discussion

In the present study, we demonstrate that IL-32γ induces the differentiation of monocytes into macrophage-like cells in the human monocytic THP-1 cell line, as well as in primary human monocytes. The macrophage-like cells after IL-32γ-induced differentiation were characterized by specific surface markers, as well as functionally by the ability to phagocytize bacteria. The effect of IL-32γ on monocyte differentiation appears to be dependent, in part, on caspase-3 activity. In addition, IL-32γ possesses the ability to switch DC differentiation induced by the combination of GM-CSF/IL-4 into a macrophage-like phenotype.

The IL-32γ isoform, which lacks any coding exon deletion, was ≈20–50 times more active in inducing monocyte differentiation than the IL-32α isoform with two coding exon deletions. IL-32α was nearly without activity in inducing macrophage differentiation; however, costimulation with MDP was needed for its activity, as previously shown for the ability of cytokine stimulation (6). Neither TLR agonists such as LPS (Fig. 1 A3 and B6) nor the NOD2 agonist MDP in the absence of serum induced differentiation by themselves (data not shown), and this may be related to their poor ability to stimulate IL-32 production in PBMCs compared with M. tuberculosis (8).

Although IL-32γ-induced monocyte differentiation was validated by the expression of distinct cell-surface markers for macrophages or DCs, IL-32γ also increased steady-state mRNA levels corresponding to these differentiation cell-surface markers (Fig. 2A). In PBMCs from seven individual donors, the surface expression of CD14 and CD1a was elevated after 3 days of exposure to IL-32γ. Whereas the increase in CD14 is an event characteristic of macrophage differentiation (16), the slight increase in CD1a expression is more characteristic of a DC phenotype (17). However, the effects of IL-32γ on the DC markers were considerably less effective than those effects of the GM-CSF/IL-4 combination of cytokines. Clearly, IL-32γ induces differentiation of monocytes into macrophage-like cells, rather than DCs. IL-32γ-induced macrophage differentiation is supported by the lack of proliferation of allogenic T cells when incubated in a mixed leukocytes culture with IL-32γ-differentiated cells (data not shown). In contrast, IL-32γ-differentiated cells displayed active functional phagocytosis, a property characteristic of macrophages.

DCs are the most specialized antigen-presenting cells during an immune response (18). GM-CSF, but particularly the combination of GM-CSF plus IL-4, induces the differentiation of monocytes into DCs (11, 13, 19). We investigated whether IL-32γ influenced this effect. Indeed, simultaneous costimulation of cells with IL-32γ and GM-CSF (Fig. 4A), or with the combination of IL-32/GM-CSF/IL-4 (Fig. 4B), shifts the differentiation from DCs to macrophage-like cells. Thus, the effects of GM-CSF/IL-4 on CD1a, CD14, or CD64 were totally or partially antagonized by IL-32γ. This is similar to the effects reported for IL-6 (14) or IFN-γ (10). However, IL-32γ reversal of GM-CSF/IL-4-induced DC differentiation into macrophages requires a closer examination. First, IL-32γ also induces CD1a expression, a DC marker, although less than GM-CSF/IL-4. Second, IL-32γ amplifies, rather than antagonizes, the effects of GM-CSF/IL-4 on CD83 expression, a DC marker usually decreased during macrophage differentiation (19). These observations demonstrate that the effects of IL-32γ are more complex. Most consistently, IL-32γ induced the differentiation of monocytes into a phenotype, which, although exhibiting a slight increase in some DC markers, induced a high level of expression of CD14. Moreover, the functional phenotype resembles more a macrophage-like cell than a DC. The consequences of these findings for the activation of the immune system in vivo remain to be elucidated.

We investigated the intracellular pathways used by IL-32γ to induce monocyte differentiation. IL-32 activates both the p38-MAPK and NF-κB pathways to induce gene transcription of proinflammatory cytokines (1), as well as activation of proinflammatory caspases such as caspase-1 (6). Based on their activity, two main categories of caspases have been identified: (i) proinflammatory caspases, such as caspase-1, -4, and -5, which were mainly involved in the cleavage of proinflammatory cytokines, such as IL-1β, (20), IL-18, and IL-33 (21); and (ii) proapoptotic caspases, such as caspase-3, -8, and -9 (22). However, data also exist that the latter group of caspases exhibit nonapoptotic functions, such as T cell activation and cell differentiation. Thus, caspase-3 and -9 (23), as well as caspase-8 (24), promote macrophage, but not DC, differentiation (23). The data presented in our study on the mechanisms of IL-32γ-induced macrophage differentiation are consistent with those of Zermati and Sordet (23, 24). For example, specific inhibitors suggest that caspase-3 activation, but not caspase-1, -8, or -9, is responsible for the ability of IL-32γ to induce monocyte differentiation. In contrast, the blockade of p38-MAPK, which strongly influenced IL-32γ-induced production of proinflammatory cytokines, did not play any role in the differentiation of monocytes by IL-32. The exact target for the caspase-3 pathway that is involved in macrophage differentiation is unclear, but several candidates have been proposed: for example, the nuclear enzyme PARP, which is cleaved during epithelial cell and erythroblast differentiation (24, 25), and the protein acinus, which is cleaved during the differentiation of U937 cells (23, 26). However, GATA-1 is cleaved during caspase-3-induced apoptosis, but not differentiation (24, 27).

In conclusion, we demonstrate that IL-32γ induces differentiation of monocytes into macrophage-like cells with characteristic surface markers and functionality as phagocytic cells. IL-32γ appears to directly induce these changes, but clearly is augmented by the activation of NOD2. In fact, we cannot completely rule out a role of NOD2 in IL-32γ activity. Unexpectedly, IL-32γ switched DC differentiation induced by GM-CSF/IL-4 to a macrophage-like phenotype. However, cells differentiated under the influence of IL-32γ also displayed markers similar to those expressed on DC, suggesting a cell-unique macrophage subtype with specific properties during infection and inflammation. IL-32 is highly expressed in rheumatoid arthritis synovial tissues, whereas IL-32 was not detected in synovia in osteoarthritis (4, 5). High expression of IL-32 in colonic epithelial cells (6, 7) suggests a role in inflammatory bowel diseases. That IL-32 contributes to macrophage differentiation during host responses to infections may be related to these clinical studies. For example, blood monocytes infiltrating an infected lung may undergo differentiation from IL-32 produced by the lung epithelial cells.

Materials and Methods

Purification of Recombinant IL-32α and IL-32γ.

Recombinant IL-32α and IL-32γ proteins were expressed in E. coli as his6 tag N-terminal fusion proteins, followed by affinity purification on a TALON affinity column (Invitrogen) as described (1). The TALON affinity-purified recombinant IL-32α and IL-32γ proteins were digested with tobacco etch virus protease (Invitrogen) for 2 h at 30°C to remove the N-terminal his6 tags. The preparations were dialyzed and subjected to ion exchange by using a 1-ml HiTrapTM QFF column on ÁKTA FPLC (Amersham Pharmacia Biosciences) using a 0- to 500-mM NaCl gradient. The eluted protein peak fractions were dialyzed against 50 mM Tris-base buffer (pH 8) and then subjected to size-exclusion chromatography (Superdex75, ÁKTA FPLC). The resulting fractions were identified by SDS/PAGE with silver staining. The final three-step-purified recombinant IL-32α and IL-32γ proteins were used for monocyte differentiation and cytokine assays. Recombinant IL-32γ and IL-32α were added to cultures of human PBMCs in the presence of 10 μg/ml polymyxin B (Sigma–Aldrich), which did not affect the production of TNFα.

PBMCs.

PBMCs were isolated from healthy human volunteers. The donors were free of prescribed and over-the-counter medications. After informed consent, venous blood was drawn from the antecubital vein into heparin tubes and processed for PBMCs as described (8). The study was approved by the Colorado Multiple Institutional Review Board.

Cell Differentiation.

THP-1 cells were obtained from American Type Culture Collection and maintained in RPMI medium 1640 with 10% FCS (HyClone). For cell differentiation studies, THP-1 cells were plated at 5 × 104 per well in six-well plates in the absence of FCS. PBMC were plated at 5 × 104 per well in 48-well plates. After 2 h incubation at 37°C, the supernatant containing nonadherent lymphocytes were discarded, and the remaining adherent monocytes were stimulated with increasing concentrations of recombinant IL-32α or IL-32γ isoforms for 3 days in the absence of FCS. Live cells were photographed at a scale of ×400 low magnification with an inverted-light microscope (DIAPHOT 300; Nikon) and at a scale of ×1,200 high magnification. LPS and MDP were purchased from Sigma–Aldrich.

RT-PCR.

Total RNA was isolated from 30 ng/ml IL-32γ-treated THP-1 cells (2 × 106 per six-well plate) and reverse transcribed by using a standard protocol. Semiquantitative PCR was performed with the following sense and reverse primers: CD1a sense, 5′-GCA TTC TGC CAT GAT TTT GAG G; reverse, 5′-AGG AGG CTC ATG GTG TGT CTT A; CD14 sense, 5′-GGT TCG GAA GAC TTA TCG ACC; reverse, 5′-ATT CTG TCT TGG ATC TTA GGC; CD64 sense, 5′-ATT TCA CTG CTC CCA CCA GCT; reverse, 5′-CAG AGT CTT CTC TTC TAG CAG; and GAPDH sense, 5′-ACC ACA GTC CAT GCC ATC AC; reverse, 5′-TCC ACC ACC CTG TTG CTG TA.

Phagocytosis.

THP-1 cells were differentiated for 3 days in the presence of IL-32γ and then were incubated for 6 h with the E. coli transformed by pGFPuv (BD Biosciences). The cells were washed with cell culture medium without FCS and then assessed by fluorescence microscope photography at a scale of ×1,000 magnification.

Flow Cytometry.

Antibodies (CD1a-PE, CD14-FITC, CD64-FITC, CD83-PE, and control IgG-PE and FITC) were purchased from eBioscience. FACS analysis of the surface expression of the macrophage and DC markers, CD14, CD1a, CD64, and CD83, was performed in freshly isolated human PBMCs stimulated for 3 days with either control medium or 30 ng/ml recombinant IL-32γ. After incubation, PBMCs were labeled with conjugated antibodies at a concentration of 3 μg/ml, and the expression of the various markers on the surface of the cells was analyzed with a fluorescent-activated scanner (FACScan; BD Biosciences).

DC Differentiation.

Human PBMCs were isolated as described. GM-CSF (50 ng/ml; Peprotech) or a combination of GM-CSF plus IL-4 (20 ng/ml; R&D Systems) was added, and the cells were cultured in sterile 4-ml polypropylene tubes. The effect of 30 ng/ml IL-32γ cotreatment on DC differentiation was assessed.

Cytokine Stimulation.

Freshly isolated human PBMCs were incubated with either control RPMI medium or 30 ng/ml IL-32γ in 96-flat well plates. After 24 h incubation at 37°C, supernatants were collected, and proinflammatory cytokines (TNFα, IL-1β, and IL-6) concentrations were measured by electrochemiluminescence using a BioVeris apparatus (28). Antibodies for biotinylation and ruthenylation as well as standards were obtained from R&D Systems. In some experiments, the MAPK inhibitor (2 μM SB203580; Calbiochem) and a pan-caspase inhibitor (10 μM z-VAD-fmk; Calbiochem) were examined. To discern between the role of the various caspases for the effects induced by IL-32, PBMCs were incubated for 3 days with IL-32γ in the presence of specific inhibitors of caspase-1, -3, -8, or -9 (Calbiochem).

Statistical Analysis.

Experiments were performed at least three times in human volunteers, and data are presented as means ± SEM. Comparisons between the groups were done by using a paired nonlogarithmic Wilcoxon test.

ACKNOWLEDGMENTS.

This work was supported by National Institutes of Health Grants AI-15614 and CA-04 6934 (to C.A.D.), an Amgen Inc. grant, Korea Science and Engineering Foundation (funded by the Korean government, Ministry of Science and Technology) Grant R01-2006-000-10837 (to S.-H.K.), and a Netherlands Organization for Scientific Research Vidi grant (to M.G.N.).

Footnotes

The authors declare no conflict of interest.

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