Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13 - PubMed (original) (raw)

Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13

H Helmby et al. J Exp Med. 2001.

Abstract

Expulsion of the gastrointestinal nematode Trichuris muris is mediated by a T helper (Th) 2 type response involving interleukin (IL)-4 and IL-13. Here we show that Th1 response-associated susceptibility involves prior activation of IL-18 and caspase-1 followed by IL-12 and interferon (IFN)-gamma in the intestine. IL-18-deficient mice are highly resistant to chronic T. muris infection and in vivo treatment of normal mice with recombinant (r)IL-18 suppresses IL-13 and IL-4 secretion but does not affect IFN-gamma. In vivo treatment of T. muris-infected IFN-gamma-deficient mice with rIL-18 demonstrated that the inhibitory effect of IL-18 on IL-13 secretion is independent of IFN-gamma. Hence, IL-18 does not function as an IFN-gamma-inducing cytokine during chronic T. muris infection but rather as a direct regulator of Th2 cytokines. These results provide the first demonstration of the critical role of IL-18 in regulating Th cell responses during gastrointestinal nematode infection.

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Figures

Figure 1

Figure 1

IL-18 is expressed earlier than IL-12 and IFN-γ in large intestine during chronic T. muris infection. mRNA for (A) IL-18, (B) IL-12p40, and (C) IFN-γ in the large intestine of susceptible AKR mice (black bar) and resistant Balb/c (white bar) mice was measured by RPA at various timepoints during T. muris infection. mRNA were normalized with respect to the housekeeping gene GAPDH. Results are expressed as fold induction over naive controls and values represent the mean value of 3–5 animals per group ± SEM. *Significantly different between AKR and Balb/c. P < 0.05.

Figure 1

Figure 1

IL-18 is expressed earlier than IL-12 and IFN-γ in large intestine during chronic T. muris infection. mRNA for (A) IL-18, (B) IL-12p40, and (C) IFN-γ in the large intestine of susceptible AKR mice (black bar) and resistant Balb/c (white bar) mice was measured by RPA at various timepoints during T. muris infection. mRNA were normalized with respect to the housekeeping gene GAPDH. Results are expressed as fold induction over naive controls and values represent the mean value of 3–5 animals per group ± SEM. *Significantly different between AKR and Balb/c. P < 0.05.

Figure 1

Figure 1

IL-18 is expressed earlier than IL-12 and IFN-γ in large intestine during chronic T. muris infection. mRNA for (A) IL-18, (B) IL-12p40, and (C) IFN-γ in the large intestine of susceptible AKR mice (black bar) and resistant Balb/c (white bar) mice was measured by RPA at various timepoints during T. muris infection. mRNA were normalized with respect to the housekeeping gene GAPDH. Results are expressed as fold induction over naive controls and values represent the mean value of 3–5 animals per group ± SEM. *Significantly different between AKR and Balb/c. P < 0.05.

Figure 2

Figure 2

Caspase-1 and IL-18Rα mRNA is expressed in large intestine during chronic T. muris infection. mRNA for (A) caspase-1 and (B) IL-18Rα in the large intestine of susceptible AKR mice (black bar) and resistant Balb/c (white bar) mice was measured by RPA at various timepoints during T. muris infection. mRNA were normalized with respect to the housekeeping gene GAPDH. Results are expressed as fold induction over naive controls and values represent the mean value of 3–5 animals per group ± SEM. *Significantly different between AKR and Balb/c. P < 0.05.

Figure 2

Figure 2

Caspase-1 and IL-18Rα mRNA is expressed in large intestine during chronic T. muris infection. mRNA for (A) caspase-1 and (B) IL-18Rα in the large intestine of susceptible AKR mice (black bar) and resistant Balb/c (white bar) mice was measured by RPA at various timepoints during T. muris infection. mRNA were normalized with respect to the housekeeping gene GAPDH. Results are expressed as fold induction over naive controls and values represent the mean value of 3–5 animals per group ± SEM. *Significantly different between AKR and Balb/c. P < 0.05.

Figure 3

Figure 3

IL-18 is expressed in the lamina propria of _T. muris_–infected large intestine. Cryosections of large intestine from naive (A and B) or day 18 infected (C and D) AKR mice were stained with rabbit anti–IL-18 antibody (B and D) or control rabbit IgG (A and C). Arrows indicate worms in the day 18 infected animals. A–D, original magnification: ×400.

Figure 4

Figure 4

IL-18 KO mice secrete high levels of IL-4 and IL-13 and are resistant to chronic T. muris infection. (A) Worm burdens from _T. muris–_infected IL-18 KO (striped bar), IL-12p40 KO (white bar), and C57Bl/6 WT (black bar) mice were assessed at days 10, 18, and 35 p.i. MLN cells were removed at day 0 (naive) and day 18 p.i. and stimulated in vitro with T. muris Ag (B–D) or LPS (E and F). Supernatants were analyzed by sandwich ELISA for the presence of (B) IFN-γ, (C) IL-4, (D) IL-13, (E) IL-12p40, and (F) IL-18. Results represent the mean value of 5–7 mice per group ± SEM. *Significantly different from WT. P < 0.05. **Significantly different from other KO. P < 0.05. nd, not detectable.

Figure 5

Figure 5

In vitro treatment with exogenous rIL-18 inhibits Ag-induced IL-13 secretion in MLN cultures from _T. muris_–infected IL-12 and IFN-γ KO mice. MLN cells from day 18 _T. muris_–infected IL-12p40 KO mice (A) and IFN-γ KO mice (B) were stimulated with T. muris Ag plus indicated doses of rIL-18 in vitro and the supernatant analyzed for IL-13, IL-4, IL-5, IL-10, and IFN-γ secretion by sandwich ELISA. Results represent the mean value of 5–7 mice per group ± SEM. *Significantly different from cultures stimulated with T. muris Ag only. P < 0.05.

Figure 5

Figure 5

In vitro treatment with exogenous rIL-18 inhibits Ag-induced IL-13 secretion in MLN cultures from _T. muris_–infected IL-12 and IFN-γ KO mice. MLN cells from day 18 _T. muris_–infected IL-12p40 KO mice (A) and IFN-γ KO mice (B) were stimulated with T. muris Ag plus indicated doses of rIL-18 in vitro and the supernatant analyzed for IL-13, IL-4, IL-5, IL-10, and IFN-γ secretion by sandwich ELISA. Results represent the mean value of 5–7 mice per group ± SEM. *Significantly different from cultures stimulated with T. muris Ag only. P < 0.05.

Figure 6

Figure 6

In vivo treatment with rIL-18 induces chronic T. muris infection without increasing Th1 responses. _T. muris_–infected C57Bl/6 mice were injected with rIL-18 (white bar) or PBS (black bar) daily for 14 d. (A) Worm burdens were assessed at days 10, 18, and 35 p.i. MLN cells were removed at day 0 (naive) and day 18 p.i. and stimulated in vitro with T. muris Ag (B–D) or LPS (E and F). Supernatants were analyzed by sandwich ELISA for the presence of (B) IFN-γ, (C) IL-4, (D) IL-13, (E) IL-12p40, and (F) IL-18. Results represent the mean value of 5–7 mice per group ± SEM. *Significantly different from PBS-treated control (P < 0.05).

Figure 7

Figure 7

In vivo treatment with rIL-18 delays worm expulsion and suppresses Ag-specific IL-13 secretion independently of IFN-γ. _T. muris_–infected IFN-γ KO mice were injected with rIL-18 (white bar) or PBS (black bar) daily for 14 d. (A) Worm burdens were assessed at day 18 p.i. and MLN cells were stimulated in vitro with T. muris Ag (B and C) or LPS (D and E). Supernatants were analyzed by sandwich ELISA for the presence of (B) IL-4, (C) IL-13, (D) IL-12p40, and (E) IL-18. Results represent the mean value of 4–5 mice per group ± SEM. *Significantly different from PBS-treated control. P < 0.05.

Comment in

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