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NFECTION AND

MMUNITY

, Dec. 1998, p. 6058–6062

0019-9567/98/$04.00 0

Vol. 66, No. 12

Lactobacilli and Streptococci Induce Interleukin-12 (IL-12), IL-18, and

Gamma Interferon Production in Human Peripheral

Blood Mononuclear Cells

MINJA MIETTINEN,

1,2

* SAMPSA MATIKAINEN,

JAANA VUOPIO-VARKILA,

JAANA PIRHONEN,

KARI VARKILA,

MASASHI KURIMOTO,

AND

ILKKA JULKUNEN

Department of Virology

and Department of Bacteriology,

National Public Health Institute, 00300 Helsinki,

and Orion Pharma, 02101 Espoo,

Finland, and Fujisaki Institute, Hayashibara Biochemical

Laboratories Inc., 675-1 Fujisaki, Okayama 702-8006, Japan

Received 8 April 1998/Returned for modiﬁcation 10 August 1998/Accepted 4 September 1998

Human peripheral blood mononuclear cells (PBMC) were stimulated with three nonpathogenic

Lactobacillus

strains and with one pathogenic

Streptococcus pyogenes

strain, and cytokine gene expression and protein pro-

duction were analyzed. All bacteria strongly induced interleukin-1 (IL-1 ), IL-6, and tumor necrosis factor

alpha mRNA expression and protein production.

S. pyogenes

was the most potent inducer of secretion of IL-12

and gamma interferon (IFN- ), and two of three

Lactobacillus

strains induced IL-12 and IFN- production. All

strains induced IL-18 protein production. IL-10 and IL-4 production was induced weakly and not at all, re-

spectively. Our data show that nonpathogenic lactobacilli and pathogenic streptococci can induce Th1 type

cytokines IL-12, IL-18, and IFN- in human PBMC.

Proinﬂammatory cytokines tumor necrosis factor alpha

(TNF- ), interleukin-1 (IL-1 ), and IL-6 as well as interfer-

ons (IFNs) are among the ﬁrst cytokines produced in response

to pathogenic bacteria (39). Cytokines produced later during

microbial infection direct responses toward either cell-medi-

ated T-helper type 1 (Th1) or humoral Th2 type immunity (2,

32). Th1 type cytokines include macrophage-derived IL-12 and

T-cell-derived gamma IFN (IFN- ). IL-12 stimulates IFN-

production in T and NK cells (10) and enhances the develop-

ment of naive CD4 T cells into Th1 type cells (2, 40). IFN-

enhances IL-12 production by phagocytic cells (21) and down-

regulates Th2 type cellular proliferation and activation. Re-

cently described IL-18 and IFN- / have been shown to con-

tribute to enhanced IFN- gene expression in T cells (28, 34)

and are thus likely to enhance Th1 type cellular responses (20,

31). IL-18 produced by activated macrophage-like cells acts

synergistically with IFN- and IL-12 in enhancing IFN- gene

expression in T cells (23, 28, 34, 41). IL-4 directly enhances the

development of Th2 type cells from naive T cells (2, 36). IL-10

produced by macrophages and lymphocytes can inhibit the

production of TNF- , IL-1 , and IL-6 (12) as well as IFN-

and IL-12 (9) and thus enhance Th2 type immune responses.

Streptococcus pyogenes,

also known as group A streptococci

(GAS), is an important human pathogen causing a wide range

of infections (37). Nonpathogenic strains of lactic acid bacteria

(LAB) such as

Lactobacillus

are part of normal human micro-

ﬂora (22), and some strains are used in the dairy industry. LAB

have also been suggested to have beneﬁcial effects on human

health (14). Intact streptococci and their cell wall components

have previously been shown to induce at least TNF- , IL-1 ,

IL-6, and IL-12 (4, 6, 8, 18, 25, 30). Similarly, LAB have been

shown to induce IFN- , IL-6, IL-10, and TNF- in human

lymphocytes (1, 24). In this study we analyzed the ability of

several live nonpathogenic LAB strains and a pathogenic GAS

* Corresponding author. Mailing address: Department of Virology,

National Public Health Institute, Mannerheimintie 166, 00300 Hel-

sinki, Finland. Phone: 358-9-47448303. Fax: 358-9-47448355. E-mail:

minja.miettinen@ktl.ﬁ.

6058

strain to induce cytokine production in peripheral blood mono-

nuclear cells (PBMC) with special interest in Th1 type cyto-

kines.

Lactobacillus rhamnosus

E509 was obtained from Arla R&D

(Stockholm, Sweden),

Lactobacillus rhamnosus

GG E522 (ATCC

53103) from Valio Ltd. R&D (Helsinki, Finland), and

Lacto-

bacillus bulgaricus

E585 from Chr. Hansen A/S (Horsholm,

Denmark).

Streptococcus pyogenes

serotype T1 IH32030 isolat-

ed from a child with bacteremia was from the collection of the

National Public Health Institute (Helsinki, Finland). All strains

were stored in skim milk at 70°C and passaged three times as

previously described (24) prior to their use in stimulation ex-

periments. Lactobacilli were grown in MRS medium and strep-

tococci were grown in TY medium supplemented with 0.2%

glucose (19). For stimulation experiments, bacteria were grown

to logarithmic growth phase and the number of bacterial cells

was determined by counting in a Petroff-Hausser counting

chamber.

Freshly collected buffy coats from healthy blood donors were

kindly provided by the Finnish Red Cross Blood Transfusion

Service (Helsinki, Finland). PBMC were isolated and cultured

as previously described (24). To minimize interindividual vari-

ation, all experiments were performed with cells obtained from

4 to 10 blood donors. PBMC were stimulated with live bacteria

in a 1:1 ratio with 6

cells/ml or with 100 ng of puriﬁed

lipopolysaccharide (LPS) per ml from

Escherichia coli

HB101,

which was kindly provided by Ilkka Helander from National

Public Health Institute (Helsinki, Finland). Cell culture super-

natants and cells were harvested at various times after stimu-

lation and pooled.

Total cellular RNA was isolated by using guanidium isothio-

cyanate and CsCl centrifugation and analyzed by the Northern

blot method as previously described (7, 16, 34). The follow-

ing cDNA probes for hybridizations were used: human TNF- ,

IL-1 , IL-6 (obtained from the American Type Culture Collec-

tion), IL-10 (kindly provided by DNAX, Palo Alto, Calif.),

IL-12 p40, IL-12 p35 (kindly provided by Ueli Gubler), IL-18

(41), and IFN- (35).

TNF- , IL-6, and IL-10 levels in cell culture supernatants

. 66, 1998

NOTES

6059

were determined by enzyme-linked immunosorbent assay

(ELISA) methods described previously (24) with sensitivi-

ties of 20 pg/ml for TNF- and IL-6 and 10 pg/ml for IL-10.

An ELISA for IL-1 with a sensitivity of 10 pg/ml was set up

with monoclonal mouse anti-human IL-1 antibody clones

508A3H12 and 508A4A2 and biotinylated mouse anti-human

IL-1 antibody clone 508A3H12. Recombinant human IL-1

was used as a standard. All IL-1 -speciﬁc reagents were pur-

chased from Medgenix Diagnostics (Fleurus, Belgium). Mono-

clonal mouse anti-human IL-4 antibody clone 3010.211, bio-

tinylated goat anti-human IL-4 antibody, and recombinant

human IL-4 purchased from R&D Systems (Abingdon, United

Kingdom) were used to set up an ELISA for IL-4 with a sen-

sitivity of 20 pg/ml. IL-12 p70 protein levels were determined

with IL-12 Quantikine HS Kit (R&D Systems) with a detection

limit of 0.5 pg/ml. IL-18 ELISA with a sensitivity of 10 pg/ml

was performed as previously described (38). Monoclonal mouse

antibody pairs and recombinant IL-18 ELISA standard were

from Hayashibara Biochemical Laboratories Inc., Fujisaki In-

stitute (Okayama, Japan). An ELISA for IFN- with a sensi-

tivity of 40 pg/ml was set up with monoclonal mouse anti-

human IFN- antibody clone 43-11 and biotinylated mouse

anti-human IFN- antibody clone 45-15 (ImmunoKontact,

Frankfurt, Germany). Recombinant human IFN- standard

was purchased from R&D Systems. IFN- / assay was done as

previously described (33) with a detection limit of 3 IU/ml.

IFN- titers in samples were assayed by vesicular stomatitis

virus plaque reduction in HEp-2 cells (5).

Cytokine production proﬁles induced by different bacteria

are shown in Fig. 1. Considerable IL-1 , IL-6, and TNF-

secretion was already seen after 6 h of stimulation of PBMC

with bacteria, and cytokine levels continued to increase up to

16 h. Bacterial strains appeared to have very similar abilities

to induce secretion of IL-1 , IL-6, and TNF- . After 6 h of

stimulation, the corresponding cytokine mRNA levels were

also high (Fig. 2) but appeared to decrease after 16 h of

stimulation except for the

L. bulgaricus

E585 strain. While no

measurable IL-4 was induced by any of the bacterial strains

(data not shown), all strains induced IL-10 protein secretion

and mRNA expression (Fig. 1 and 2) with slower kinetics than

those of proinﬂammatory cytokines. No measurable IFN-

production was seen in PBMC by LAB or GAS (data not

shown). The kinetics of IL-12 and IFN- secretion induced by

LAB and GAS was relatively slow and differed from that of

IL-18. IL-18 protein production was already seen in the cell

culture supernatant after 6 h of stimulation, whereas IL-12 and

IFN- were detected only after 16 h of stimulation (Fig. 1). No

IL-18 mRNA induction was detected in PBMC by any of the

stimulants (data not shown). There were certain strain-speciﬁc

differences in Th1 type cytokine production.

L. rhamnosus

E509 and

S. pyogenes

IH32030 stimulation elicited the highest

secreted IL-12 p70 and IFN- protein levels (Fig. 1). Accord-

ingly, in Northern blot analysis, these bacteria were the best

inducers of IL-12 and IFN- mRNAs. All bacteria were able to

induce IL-12 p35, IL-12 p40, and IFN- mRNAs except for

L. bulgaricus

E585, which was a poor inducer of IL-12 p35 and

IFN- gene expression (Fig. 2).

To analyze cytokine gene expression in more detail, PBMC

were stimulated with LPS or with live

L. rhamnosus

E522 or

S. pyogenes

IH32030 for 2, 6, and 16 h. Cytokine mRNA ex-

pression in

S. pyogenes

IH32030-stimulated PBMC is shown in

Fig. 3. Induction of TNF- , IL-1 , and IL-6 mRNAs peaked at

2 h. IL-10 mRNA expression, on the contrary, peaked at 16 h.

Weak induction of IL-12 p40 mRNA was seen after 2 h of

stimulation. Both IL-12-speciﬁc mRNA chains p35 and p40

were strongly induced at 6 h by

S. pyogenes

IH32030 and

FIG. 1. ELISA measurements of cytokine production in PBMC induced by

L. rhamnosus

E509,

L. rhamnosus

E522,

L. bulgaricus

E585, and

S. pyogenes

IH32030. PBMC (6 10

/ml) were stimulated with 6 10

live bacteria per ml

for 6 h (hatched bars) or 16 h (black bars). Results are means of three indepen-

dent experiments, each done with PBMC from three or four donors. Error bars

represent standard deviations of the means.

appeared to decrease at 16 h. High IL-12 p40 and p35 mRNA

levels at 6 h coincided with strong expression of IFN- . IFN-

mRNA levels were high longer than IL-12 p35 and p40 levels.

Cytokine mRNA expression levels after

L. rhamnosus

E522

stimulation are shown in Fig. 4. IL-1 mRNA levels were high

at 2 h but started to decline thereafter.

L. rhamnosus

E522-

induced TNF- and IL-6 mRNA levels peaked at 6 h com-

pared to the peak at 2 h by

S. pyogenes

IH32030. The expres-

sion of IL-10 and IL-12 p35 and p40 mRNAs were highest after

16 h of stimulation with

L. rhamnosus

E522. Some IL-12 p40

mRNA expression was seen already at 6 h, while IL-12 p35

mRNA expression was not seen then. IFN- induction by E522

L. rhamnosus

was detectable at 6 h, and high levels were seen

after 16 h of stimulation.

Nonpathogenic LAB and pathogenic GAS did not appear to

differ in their potency to induce TNF- , IL-1 , and IL-6 se-

cretion, and the kinetics of mRNA induction was fast, as shown

by strong mRNA accumulation after only 2 h of stimulation.

Similarities in the kinetics of TNF- , IL-1 , and IL-6 induction

and production by LPS, LAB, and GAS suggest that the most

promising candidates for cells rapidly responding and being

responsible for production of these cytokines are monocytes,

which are known to respond rapidly after encountering patho-

genic bacteria or bacterial components such as LPS and as a

result produce proinﬂammatory cytokines (39).

LPS, LAB, or GAS did not induce any detectable IL-4 pro-

duction in PBMC, while some IL-10 production was seen.

Since the development of Th2 cells requires IL-4 (36), the lack

6060

NOTES

NFECT

. I

MMUN

S. pyogenes

and

L. rhamnosus

E522 induced IL-12 p35 and p40

and IFN- mRNA expression similarly, these bacteria did so at

different time points. It is possible that

S. pyogenes

as a patho-

gen interacts more efﬁciently with PBMC than nonpathogenic

LAB do. Cell size of bacterial strains used in our study varies,

and the ratio of possible antigenic structures on bacterial cells

could be different. These factors may affect interactions of

LAB and GAS with PBMC and hence their cytokine produc-

tion. Efﬁcient interactions between GAS and PBMC could

lead to a faster production of Th1 type cytokines by GAS than

by LAB.

So far the only bacterium reported to induce IL-18 is

Pro-

pionibacterium acnes

(28). In the present work, we show that

nonpathogenic lactobacilli and pathogenic

S. pyogenes

are

equally potent in inducing IL-18 production in PBMC. IL-18

production in PBMC was induced by all

Lactobacillus

strains

and

S. pyogenes,

and the kinetics of IL-18 production was fast,

resembling those of proinﬂammatory cytokines. The similarity

in the kinetics of IL-18 and proinﬂammatory cytokine produc-

tion could reﬂect the recently suggested proinﬂammatory na-

ture of IL-18 (29). While IL-18 secretion was induced by both

LAB and GAS, the levels of IL-18 remained relatively low. It

is possible that the amount of IL-18 produced by monocytes is

small or that the vast majority of T (and B) cells present in

FIG. 2. Northern blot analysis of cytokine production in PBMC induced by

LPS,

L. rhamnosus

E509,

L. rhamnosus

E522,

L. bulgaricus

E585, and

S. pyogenes

IH32030. PBMC (6 10

/ml) from four donors were stimulated with 6 10

live

bacteria per ml or with 100 ng of LPS per ml for 6 or 16 h.

of IL-4 production in LAB- and GAS-stimulated PBMC could

suggest the lack of further Th2 type response. Our results on

IL-4 and IL-10 production are in accordance with previous

ﬁndings in which inactivated

S. pyogenes

preparations were

found to induce IL-10 but not IL-4 (13). The kinetics of IL-10

induction and production was slower than those of proinﬂam-

matory cytokines, which is also consistent with previous obser-

vations (12).

Pathogenic streptococci and their cell walls or secreted com-

ponents have been used to study Th1 type cytokine production

in various cellular systems. Lipoteichoic acids of

Streptococcus

pneumoniae

and

S. pyogenes

as well as heat-killed

S. pneumo-

niae

have been shown to induce IL-12 in THP-1 cells (8). Su-

perantigens from GAS have been shown to induce IFN- in

human PBMC (26, 27). In addition, nonpathogenic lactobacilli

and streptococci have been shown to induce IFN- production

in human lymphocytes and PBMC (1, 11). We show here that

both live nonpathogenic LAB and pathogenic GAS induce IL-

12 and IFN- production in human PBMC similarly. However,

some kinetic differences in cytokine induction were seen.

S. py-

ogenes

was also a more potent inducer of IL-12 and IFN-

secretion than LAB strains. Differences in the kinetics of IL-12

and IFN- induction could be due to differential use of leuko-

cyte cell surface receptors by LPS, LAB, and GAS. While

FIG. 3. Kinetics of cytokine production in PBMC induced by

S. pyogenes

IH32030. PBMC (6 10

/ml) from four donors were stimulated with 6 10

live

bacteria per ml or with 100 ng of LPS per ml for 2, 6, or 16 h and then prepared

for Northern blot analysis.

. 66, 1998

NOTES

6061

bacteria including nonpathogenic ones could elicit a Th1 type

immune response.

This work was supported by the Jenny and Antti Wihuri Foundation,

the Medical Research Council of the Finnish Academy, Nordic Indus-

trial Fund project P93176, and the Sigrid Juselius Foundation.

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E. I. Tuomanen

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