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Immunology. Aug 2004; 112(4): 674–680.
PMCID: PMC1782533

Differential production of interleukin-10 and interleukin-12 in mononuclear cells from leprosy patients with a Toll-like receptor 2 mutation

Abstract

Toll-like receptor 2 (TLR2) is a key mediator of the immune response to mycobacterial infections, and mutations in TLR2 have been shown to confer susceptibility to infection with mycobacteria. This study investigated the profiles of cytokines, such as interferon (IFN)-γ, interleukin (IL)-10, IL-12 and tumour necrosis factor (TNF)-α in response to Mycobacterium leprae in peripheral blood mononuclear cells (PBMC) with the TLR2 mutation Arg677Trp, a recently reported polymorphism that is associated with lepromatous leprosy. In leprosy patients with the TLR2 mutation, production of IL-2, IL-12, IFN-γ, and TNF-α by M. leprae-stimulated PBMC were significantly decreased compared with that in groups with wild-type TLR2. However, the cells from patients with the TLR2 mutation showed significantly increased production of IL-10. There was no significant difference in IL-4 production between the mutant and wild-type during stimulation. Thus, these results suggest that the TLR2 signal pathway plays a critical role in the alteration of cytokine profiles in PBMC from leprosy patients and the TLR2 mutation Arg677Trp provides a mechanism for the poor cellular immune response associated with lepromatous leprosy.

Keywords: cytokines, leprosy, mononuclear cells, mutation, Toll-like receptor 2

Introduction

Mycobacterial infections such as leprosy and tuberculosis have been a leading global health threat. Incomplete understanding of the nature of protective immune response has hampered the discovery of the exact pathogenesis. Adequate activation of tissue macrophages is thought to be the key to the ultimate eradication of intracellular mycobacteria. The cell-mediated immune response is an important aspect of host resistance to mycobacterial infection and is thought to be tightly regulated by a balance between the type 1 cytokines including interleukin (IL)-2, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and IL-12 and the type 2 counterparts such as IL-4, IL-6 and IL-10. IL-12 induces T helper 1 (Th1) differentiation and IFN-γ release from Th1 and natural killer (NK) cells. IFN-γ plays a role in antimycobacterial immune responses via activating macrophages.1 TNF-α is capable of many pro-inflammatory activities including macrophages activation.2 In contrast, IL-10 has been shown to be a counter-regulatory cytokine that can affect the immunomodulatory effects of IL-12.3 The production of IL-10 during bacterial infection has been shown to suppress production of inflammatory mediators and aid in the development of Th2 immunity.

The ability of the host to rapidly detect invading pathogens is an important feature of the innate immune system and is mediated in part by pattern recognition receptors that recognize various classes of microbial ligands. Toll-like receptors (TLRs) are a set of innate immune receptors that recognize structures common to many different pathogens and are required for the optimal induction of innate immunity against microbial infection.48 In particular, TLR2 has been shown to be involved in the recognition of mycobacterial lipoproteins.9,10

To study the role of TLR2 in mycobacterial infectious disease, we chose leprosy as a model because of its spectrum of clinical manifestations that correlate with the level of cell-mediated immunity (CMI) to Mycobacterium leprae. Patients with the tuberculoid form (TT) are relatively resistant to the pathogen; the infection is localized and the lesions are characterized by expression of the type-1 cytokines characteristic of cell-mediated immunity. In contrast, patients with lepromatous leprosy (LL) are relatively susceptible to the pathogen; infection is systemically disseminated and the lesions are characterized by the type-2 cytokines characteristic of humoral responses.11 The precise mechanism of cytokine patterns according to leprosy type is not clear.

Polymorphisms in the human TLR2 and TLR4 genes are correlated with an increased susceptibility to pathogenic bacterial infection.12,13 Although information about allelic variants of human TLR genes is still very limited, mutations in both the ectodomains and the cytosolic domains of TLR have been identified. Mutations in the TLR4 at residues 299 and 399 were shown to be associated with hyporesponsiveness to inhaled endotoxin in human12 and it was suggested that the TLR2 mutation Arg753Gln could be a risk factor the developing septic shock after infection by Gram-positive bacteria.13

Past studies have shown the data on a polymorphism (Arg677Trp) of TLR2 in lepromatous leprosy patients (Fig. 1) and the relation between the susceptibility and TLR2 mutation in mycobacterial infection14,15 and this mutation was not able to mediate nuclear factor-κB activation in response to M. leprae cell components.16 Especially, this polymorphism of TLR2 was involved in only LL, not TT and healthy controls.14 Thus, we hypothesize that TLR2 may play a key role in the determination of the type of leprosy.

Figure 1
The point mutation of the tlr2 gene in lepromatous leprosy. Sequence comparison of TLR2 wild type, TLR2 (WT) and mutant, TLR2 (M). The mutant had one amino acid replacement (amino acid residue 677) in the intracellular domain compared with wild type. ...

The present study was undertaken with the aim of understanding the role of TLR2 in the alteration of cytokine profiles in peripheral blood mononuclear cells (PBMC) from leprosy patients with TLR2 mutation. We examined IL-10 and IL-12 production by PBMC with TLR2 mutation in response to M. leprae and tested the role of TLR2 in the alteration of cytokine profiles in PBMC to explain the cytokine differences observed in the clinical manifestations of leprosy. Following in vitro M. leprae stimulation, the production of cytokines IFN-γ, TNF, and IL-4, as well as regulatory cytokines, IL-10 and IL-12 was quantified in each cDNA sample using reverse transcription–polymerase chain reaction (RT–PCR) assay and enzyme-linked immunosorbent assay (ELISA).

Materials and methods

Study subjects

Our study subject population consisted of 10 healthy volunteers and 15 leprosy patients conducted by the Institute of Hansen's Disease (Seoul, Korea). The leprosy patients were eight LL and seven TT, and they were classified according to the clinical and pathological criteria of Ridley and Jopling.17 Patients were successfully treated with antileprosy drugs and no acid-fast bacilli (M. leprae) were observed, currently. Both healthy control and patients had been previously genotyped for a study on TLR2 polymorphisms. Five leprosy patients had the TLR2 mutation (Arg677Trp); the mutation was not found in TT and normal healthy controls. The patient profiles are shown in Table 1.

Table 1
Characteristics of the study group

Reagents, ELISA kit, and antibodies

The following materials were obtained as indicated: fetal bovine serum (FBS) from Hyclone (Logan, UT), lipopolysaccharide (LPS; Escherichia coli O111: B4) from Sigma Chemical Co. (St Louis, MO). The ELISA kits for IL-2, IL-4, IL-10, IL-12p40, IL-12p70, TNF-α and IFN-γ were obtained from Pharmingen (San Diego, CA). For flow cytometric analysis, phycoerythrin (PE)-labelled anti-human Toll-like receptor 2 (TLR2) was purchased from eBioscience (San Diego, CA) and allophycocyanin (APC)-labelled anti-CD3 and fluorescein isothiocyanate (FITC)-labelled anti-CD14 were purchased from Becton Dickinson (Oxnard, CA).

Isolation of M. leprae from the infected foot pads of nude mice

Foot-pad granuloma from M. leprae-infected nude mice was dissected, soaked in iodine 1% solution, and chopped finely with no. 10 and 15 disposable scalpels. The sample was then homogenized in 2 ml Dulbecco's phosphate-buffered saline (DPBS, Sigma) with 25–30 glass beads (3 mm in diameter) for 3 min in a Mickle homogenizer (Mickle Laboratory Engineering Co., Guildford, UK). A part of the supernatant was stained with Ziehl–Neelsen's stain for acid-fast bacilli which were enumerated by the procedure of Shepard and McRae.18

Preparation and stimulation of PBMC

PBMC were isolated by standard density gradient centrifugation with Ficoll-Paque (Amersham Pharmacia Biotech, Amersham, UK) from heparinized whole blood or buffy-coat of leprosy patients and normal healthy donors. PBMC were suspended at a density of 2 × 107 viable cells/ml in RPMI-1640 medium containing 10% FBS, 2 mm glutamine, 100 μg/ml gentamicin (Life Technologies, Grand Island, NY). The cells were then stimulated with and without M. leprae (2 × 108 bacilli) or LPS (100 ng) for 18 hr.

Flow cytometry

Cell suspensions were stained for analysis by flow cytometry in U-bottomed tubes (2 × 105 cells per test). Flow cytometric data were collected using a FACS Calibur machine (Becton Dickinson) and analyzed with CELL QUEST software (Becton Dickinson).

Cytokine assay

After receiving informed consent, mononuclear cells were prepared both from leprosy patients and healthy donors as above described and treated with M. leprae and LPS. Cell culture supernatants were collected, cleared by centrifugation, and stored at −70 until required. Duplicate samples of supernatants were assayed with commercial assay kits for IL-2, IL-4, IL-10, IL-12p40, IL-12p70, TNF-α and IFN-γ, according to the manufacturer's instructions. Cytokine concentrations in the samples were calculated with standard curves generated from recombinant cytokines, and the results were expressed in picograms per millilitre.

Total RNA isolation, cDNA synthesis, and RT–PCR

Total RNA was extracted using High pure RNA isolation kit from Roche (Roche Diagnostic Gmbh, Mannheim, Germany) by following the manufacturer's instructions. cDNA synthesis and RT–PCR were performed using an RNA PCR kit from Perkin-Elmer (Applied Biosystems Division, Foster City, CA). The amplified PCR products were separated by electrophoresis on a 2% agarose gel and visualized by ethidium bromide staining. Quantitative analysis of bands were conducted by phosphoimager with Bio-1D V.97 software for Windows 95 (Vilber Lourmat, Marne La Vallée, France). The primers were: β-actin sense, 5′-ATGGAGAAAATCTGGCACCA-3′; β-actin antisense, 5′-AATGGTGATGACCTGGCCCT-3′; hTLR2 sense, 5′-ACCTTATGGTCCAGGAGCTG-3′; hTLR2 antisense, 5′- TGCACCACTCACTCTTCACA-3′; hTNF-α sense, 5′-CCATGAGCACTGAAAGCATG-3′; hTNF-α antisense, 5′-TCACAGGGCAATGATCCCAA-3′.

Statistical analysis

The results are presented as the mean ± standard error of the mean. Statistical significance was calculated using Student's t-test and a P-value of less than 0·05 was considered significant. Statistically significant data are indicated in the figure by asterisk, and the P-values are listed in the figure legends.

Results

Cytokine production of PBMC with TLR2 mutation

PBMC with TLR2 mutation or wild-type were stimulated with M. leprae or LPS. Cytokines were measures after 18 h of stimulation. The production of the Th1 cytokine IL-2, IL-12, IFN-γ, and TNF-α was significantly lower in PBMC of TLR2 mutation than it was in wild-type PBMC after stimulation (Table 2 and Figs 2 and and3).3). PBMC from healthy control with TLR2 wild-type showed the similar results with PBMC from patients with TLR2 wild-type. In contrast with the group with TLR2 wild-type, the patient with TLR2 mutation showed a twofold increase of IL-10. IL-4, one of the Th2 cytokines, was not significantly different between TLR2 wild-type and mutant. Tuberculosis purified protein derivatives (PPD; Statens Serum Institute, Denmark) was used as another stimulus, and the results were similar with data shown in the M. leprae strain (data not shown).

Figure 2
IL-10 and IL-12 production of PBMC from leprosy patients with or without TLR2 mutation (Arg677Trp). IL-10 and IL-12 in unstimulated cells were below the level of detection (<25 and 20 pg/ml, respectively). Mononuclear cells (2 × 107 cells) ...
Figure 3
Production of TNF in PBMC from leprosy patients with or without TLR2 mutation (Arg677Trp). Mononuclear cells (2 × 107 cells) were stimulated with M. leprae (2 × 108 bacilli) or LPS (100 ng) for 18 hr. (a) Supernatants were harvested to ...
Table 2
Levels of cytokines induced by M. leprae from PBMC of leprosy patients with or without TLR2 mutation (TLR2Arg677Trp)

Role of TLR2 mutation on IL-10 and IL-12 production

Because IL-12 and IL-10 have distinct effects in Th1-type immune responses, we compared the levels of IL-12 and IL-10 in PBMC after stimulation with M. leprae and LPS. After stimulation for 18 hr, the cytokine content was determined by ELISA.

The bioactive form of IL-12 is a p70 heterodimer composed of p40 and p35 subunits. Because IL-12p70 is secreted at lower levels than IL-12p40, we performed experiments using both cytokines. However, there is no difference in the levels between IL-12p40 and IL-12p70. We found that mononuclear cells from TLR2 wild-type and mutant produced both IL-12 and IL-10 after stimulation with M. leprae. Cells with TLR wild-type produced comparable amounts of IL-12, but little IL-10. However, in individuals with TLR2 mutant cells produced more IL-10 than IL-12 (Fig. 2).

Our data indicated that TLR2 mutation is associated with the differential production of IL-10 and IL-12.

Role of TLR2 mutation for the production of TNF-α

For proper or effective antimycobacterial activities of macrophages, stimulation by pro-inflammatory cytokine, such as TNF-α, is crucial. In contrast, anti-inflammatory cytokines, such as IL-4 and IL-10, inhibit the cellular mechanisms important for antimycobacterial defence. We previously demonstrated that upon exposure to M. leprae lysate, monocytes are stimulated to produce the pro-inflammatory cytokine, TNF-α, in a TLR2-dependent manner.15 As TLR2 mediates the cellular production of inflammatory cytokines, we thus examined whether a difference exists in the production of TNF-α of PBMC with TLR2 mutation or wild-type following infection with M. leprae.

As shown in Fig. 3(a) PBMC from TLR2 wild-type released high amounts of TNF-α in response to a challenge with M. leprae or LPS, whereas the production of TNF-α was lower in TLR2 mutant PBMC stimulated with M. leprae. However, there were no significant differences between wild-type and mutant after stimulation with LPS. It is likely that this is due to the fact that immune response triggered by LPS is mediated by mainly TLR4, not TLR2. The expression of TNF-α by RT–PCR showed the result with similar data (Fig. 3b).

TLR2 expression on monocytes from patients with TLR2 mutation (TLR2 Arg677Trp)

We investigated the expression of TLR2 on monocytes (CD14+ cells) from patients with TLR2 mutation (TLR2 Arg677Trp) to examine if this polymorphism affects the expression of TLR2. Fluorescence-activated cell sorting analysis showed the expression of TLR2 on monocytes from leprosy patients after stimulation with M. leprae. The level of TLR2 expression on monocytes from both groups with TLR2 wild-type and mutant was increased from 1·27% and 1·20% to 9·07% and 8·79%, respectively, following the stimulation of M. leprae (Fig. 4a). We also investigated the expression of TLR2 on lymphocytes (CD3+ cells), but the same results were showed (data not shown). RT–PCR analysis showed the same result (Fig. 4b).

Figure 4
TLR2 expression of PBMC from leprosy patients with or without TLR2 mutation (Arg677Trp). Mononuclear cells (2 × 107 cells) were stimulated with M. leprae (2 × 108 bacilli) for 18 hr. (a) Expression of TLR2 and CD14. After stimulation with ...

Discussion

TLR2 plays an essential role in the innate immune response to M. leprae and a polymorphism of TLR2 (Arg677Trp) that was associated with lepromatous leprosy is unable to respond to M. leprae stimulation.15,16 A major aim of this study was to define how TLR2 mutation affects initial production of both Th1 and Th2 cytokines by PBMC stimulated with M. leprae. We investigated the cytokine profiles in PBMC from leprosy patients with TLR2 mutation (Arg677Trp).

The immunodeficiency present in the patients with LL is characterized by the limited proliferation of T lymphocytes, and is explained in part by the impaired synthesis of IL-2. LL patients also appeared to have defective production of IFN-γ when peripheral-blood-derived lymphocytes were stimulated with M. leprae.11

IFN-γ plays a critical role in host defence against intracellular infections, including mycobacterial infection.1921 It is widely believed that IL-12 released from activated macrophages stimulates Th1 cells to release IFN-γ, by potently activating macrophages as well as T cells. IL-12 promotes CMI to intracellular pathogens, including M. leprae, by augmenting Th 1 response.10,22

In our previous study, we reported a novel polymorphism of the TLR2 gene that may be associated with an increased risk for M. leprae in the patients with the mutation (Fig. 1).14 The TLR2 polymorphism has a frequency of about 22% in the populations tested and changes a highly conserved arginine residue to tryptophan. Only some of LL patients, not the TT patients and normal controls, were shown to correspond to a point mutation (missense mutation) in the intracellular domain of the Toll-like receptor-2 gene (tlr2), predicted to replace arginine with tryptophan at position 677.

Our results in this study demonstrated that TLR2 mutation was associated with the determination of the type of leprosy by differentially producing IL-10 and IL-12 in PBMC against M. leprae. In comparing the two types of cells with or without the TLR2 mutant, mononuclear cells with the TLR2 mutant showed significantly lower production of IL-12 and TNF-α. The mononuclear cells with the TLR2 mutation showed higher production of IL-10 compared with those with TLR2 wild-type. Thus, the results in this study suggest that TLR2 plays a critical role in the alteration of cytokine profiles in PBMC from leprosy patients and the impaired function of the TLR2 variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy. However, it is not clear how this mutation is connected to this process.

While TLR4 seems to be mainly highly specific for LPS-mediated signalling, TLR2 can respond to a variety of different bacterial cell wall components. Interestingly, Fig. 2 showed that the TLR2Arg677 Trp polymorphism discovered by our group affects the LPS response (Table 2 and Fig. 2b), and in particular partially inhibited the production of IL-12 in response to the LPS-like response to M. leprae. Our results were different from other results indicating that TLR2Arg753Gln, another polymorphism of TLR2, does not affect the LPS response in vitro.13 It seems that there are some differences between two groups, because our results were from primary cells of individuals that carry the Arg677Trp polymorphism and the results of other group were from reconstitution system (transfection assay). Although there are a number of limitations to the study with clinical samples, it is important to confirm the understanding of the relationships between gene polymorphisms and disease susceptibility in primary cells from patients.

For many pathogens, the outcome of the immune response to the infection depends on the pattern of cytokines produced by T cells, a central part of the adaptive immune response. The T-cell pattern is directed, in part, by the balance of cytokines produced by cells of the innate immune system. Monocytes, macrophages and lymphocytes participate in the process by secreting the cross-regulatory cytokines IL-12 and IL-10. IL-12 is a powerful signal for the generation of Th1 cytokine responses, whereas IL-10 can inhibit both the release of IL-12 and be the effector of IL-12 on T cells, thus down-regulating Th1 responses. Because of the ability of IL-12 to promote protective immunity, its expression may be critical for successful development of vaccines against intracellular pathogens, including M. leprae and M. tuberculosis.10 Thus, an understanding of the regulated expression of IL-12 in macrophages may provide an insight into the pathogenesis of infection and inflammatory diseases and may suggest novel approaches for altering immune responses.

Whereas the ability of IL-10 and IL-12 to regulate qualitative and quantitative aspects of cell-mediated and humoral immunity are well defined, the underlying cellular mechanisms responsible for dictating their initial induction are an area of intense investigation.

Recently, it was reported that the phosphatidylinositol 3-kinase-Akt pathway23 and CpG DNA24 involved in TLR signalling differentially regulate IL-10 and IL-12 production by various stimuli. Moreover, Qi et al. suggested that microbe-specific information sensed through different TLRs by dendritic cells (DC) is linked to differential Th priming through DC-derived cytokines.25

Our results have shown the differential production of Th1 cytokines (IL-2, IL-12, IFN-γ, and TNF-α), and Th2 cytokines (IL-4 and IL-10) in leprosy patients with TLR2 mutation. Although the role of TLR2 in regulating IL-10 and IL-12 is not currently known, these findings suggest that the mutation of TLR2 may be, in part, responsible for the skewing of Th1- and Th2-type immune responses observed in leprosy.

In addition, we examined the TLR2 expression on PBMC from patients with TLR2 mutation. TLRs were expressed in monocytes, T lymphocytes and dendritic cells.26 The level of TLR2 expression on CD14+ cells (monocytes) from both patients with TLR2 wild-type and mutant (TLR2R677W) was increased after stimulating of M. leprae. The same results on TLR2 expression were also shown on CD3+ T lymphocytes (data not shown). Because this mutation is located at the intracellular domain of TLR2, it likely affects the signalling function of the molecule, rather than ligand binding and expression itself and that this polymorphism is not necessary for the expression of TLR2. Thus, differential signals channelled through TLR2 are likely to be the crucial cue for both of the innate and adaptive immunity.

In conclusion, one of the key functional parameters determining the outcome of immune response to infectious pathogens is the nature of the cytokines produced by immune cells. The role of TLR2 on cytokine pattern shown in this study is likely to contribute to the pathogenesis of other infectious disease.

We also used tuberculosis PPD as another stimuli, and the results were similar to the data shown in M. leprae strain. Therefore, we suggest it is possible that cytokine responses observed in this study are not antigen specific but mycobacteria specific. Although mycobacteria have the evading mechanisms of host defence, they express pathogen associated molecular patterns, such as lipoprotein and lipoglycan that are recognized by cells of the innate immune system through the family of TLRs. Future study should include the analysis of cell wall components of mycobacteria and how they correlate with immune modulation.

Acknowledgments

This work was supported by the Catholic Medical Center Research Foundation 2002.

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