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Infection and Immunity, July 2006, p. 4370-4374, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.00422-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Responses to Leishmania donovani in Mice Deficient in Interleukin-12 (IL-12), IL-12/IL-23, or IL-18

Henry W. Murray,1* Christine W. Tsai,1 Jianguo Liu,2 and Xiaojing Ma2

Departments of Medicine,1 Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 100212

Received 15 March 2006/ Returned for modification 19 April 2006/ Accepted 21 April 2006


   ABSTRACT
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Interleukin-12 (IL-12) orchestrates acquired resistance in intracellular Leishmania donovani infection in the liver, inducing gamma interferon and, in turn, macrophage activation and parasite killing. Nevertheless, testing in IL-18–/– mice compared to wild-type mice and in IL-12p40–/– compared to IL-12p35–/– mice also suggested both early-acting (IL-18) and late-acting (IL-23) antileishmanial effects independent of IL-12.


   TEXT
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In experimental Leishmania donovani infection in the liver, granuloma assembly, activated macrophage parasite killing, and responses to conventional antimony (Sb) chemotherapy are regulated by mechanisms which govern gamma interferon (IFN-{gamma}) production (7, 19, 21, 35). Although capable of IFN-{gamma}-independent action (2, 18, 32), interleukin-12 (IL-12 [IL-12p70, composed of p35 and p40 subunits]) is a primary stimulus for L. donovani-induced IFN-{gamma} (2, 15, 17, 32); thus, each of the preceding antileishmanial effects is also regulated by IL-12 (2, 17). Nevertheless, other cytokines, acting alone or with IL-12, also help to shape acquired resistance and/or promote IFN-{gamma} secretion (3, 5, 8, 13, 14, 16, 18, 30, 31, 33, 34); IL-2, IL-4, and tumor necrosis factor, for example, have already been identified as being active in the initial defense against L. donovani (14, 20, 29).

To test roles of two other potential IFN-{gamma}-inducing cytokines, IL-23 and IL-18 (8, 13, 18, 25, 26, 30, 31), the following types of female mice were infected with 1.5 x 107 intravenously injected, hamster spleen-derived L. donovani amastigotes (1 Sudan strain): (a) wild type (WT), IL-12p35–/– (deficient in IL-12 alone), IL-12p40–/– (deficient in IL-12 and IL-23, the latter composed of p40 and p19 (25) and IFN-{gamma}–/– (BALB/c background), and (b) WT, IL-18–/– and IFN-{gamma}–/– (C57BL/6 background) (24). WT BALB/c and C57BL/6 mice respond similarly to L. donovani (21) and, as anticipated, showed initial susceptibility and then self-cure by week 8 (Fig. 1). This acquired resistance response is associated with induction of IL-12p40 and IFN-{gamma} mRNA expression in liver tissue (2, 11, 22) and increases in IFN-{gamma} and IL-12p40 and p70 in serum at weeks 2 to 4 (17, 23, 27, 29, 32). In livers of BALB/c mice, used here as representative of WT animals, p19 mRNA (IL-23 marker) was detected in uninfected mice, and expression was not increased by L. donovani infection (week 3, semiquantitative reverse transcription-PCR normalized to HRPT expression, not shown). While IL-18 mRNA was also expressed constitutively (10), its expression increased at weeks 2 and 4 in infected animals (Fig. 2).


Figure 1
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  		FIG. 1. Outcome of L. donovani infection in the liver measured microscopically in tissue imprints and expressed as Leishman-Donovan units (LDU) (24). Results are from two to four experiments in each group of mice and indicate mean ± standard error of the mean values for 7 to 14 mice per time point. At weeks 8 and 12, LDU results for WT mice were 112 ± 21 and 2 ± 1, respectively, in BALB/c mice (A) and 78 ± 15 and 28 ± 6, respectively, in C57BL/6 mice (B). For panel A, the P value is <0.05 for p40–/– and p35–/– mice versus WT mice at weeks 3 to 12. For panel B, the P value is <0.05 for IL-18–/– versus WT mice at weeks 2, 4, and 8.

 

Figure 2
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  		FIG. 2. IL-18 mRNA expression in WT BALB/c liver tissue on days +14 and +28 after infection. Real-time PCR results, normalized to GAPDH (glyceraldehyde-3-phosphate dehydrogenase) expression, are for three mice per group in the single experiment performed, and indicate mean n-fold increases (±standard errors of the means) relative to the day 0 result, arbitrarily assigned the value of 1. The P values were <0.03 at days +14 and +28 versus day 0.

 
IL-12p35–/– mice show enhanced susceptibility to L. donovani (18, 24) and, as illustrated in Fig. 1A, developed high-level, noncuring infection. Since IL-23 and IL-18 are preserved in p35–/– mice (1, 9, 13, 26), apparently, neither could compensate for IL-12's overall antileishmanial effect (2, 12, 17, 18). In addition, initial kinetics of parasite replication in IL-12p35–/– mice and IL-12p40–/– mice were similar, indicating little consequence from the additional absence of IL-23 in p40–/– mice. However, at week 12, a late-acting IL-23 effect was uncovered, as parasite burdens were appreciably higher in p40–/– mice (P < 0.05), reaching that level at week 12 in IFN-{gamma}–/– mice (Fig. 1A).

In contrast, IL-18–/– mice controlled liver infection by week 12 (Fig. 1B). However, susceptibility to L. donovani was clearly increased initially, compared to WT animals (e.g., at week 4), and liver parasite burdens were still 13-fold higher at week 8 in IL-18–/– mice. These results point to a separate IL-12/IL-23-independent role for IL-18, since IL-12 and presumably IL-23 expression is intact in IL-18-deficient mice (12, 26). While the latter controlled infection at week 12, IFN-{gamma}–/– mice (19, 24) infected in parallel did not (Fig. 1B), indicating stimuli other than IL-18 for IFN-{gamma} production in this model (see the next paragraph).

Increased IFN-{gamma} levels were detected in serum on days +14 and +21 in both infected BALB/c and C57BL/6 WT mice (Fig. 3). Attesting to IL-12's role in IFN-{gamma} secretion in L. donovani infection (2, 15, 17, 28), serum IFN-{gamma} was undetectable initially in both IL-12p35–/– and p40–/– animals, although low levels were detected on day +28 at 20 ± 19 and 8 ± 8 pg/ml, respectively (four mice per group). In contrast, IFN-{gamma} levels in infected IL-18–/– mice were not different from WT controls (P > 0.05). While the measuring of IFN-{gamma} in serum is a useful marker of Th1-cell-type responses, the physiologic implication of activity in serum (versus in situ IFN-{gamma} expression at the infected tissue focus) is unknown. However, in view of initially enhanced susceptibility to L. donovani in IL-18–/– mice (Fig. 1B), preserved IFN-{gamma} secretion suggested an early-acting, IFN-{gamma}-independent antileishmanial effect for endogenous IL-18, as reported in other models (26). Such a mechanism might involve the effects of tumor necrosis factor (32).


Figure 3
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  		FIG. 3. Serum IFN-{gamma} levels before and 14 and 21 days after L. donovani infection. Enzyme-linked immunosorbent assay results in panels A and B indicate mean ± standard error of the mean values for four mice per group from the single experiment performed. In calculating mean values, an enzyme-linked immunosorbent assay result of <31 pg/ml (lower limit of detection) was arbitrarily assigned the value of 0.

 
In addition to macrophage activation and control of infection, the IFN-{gamma}-mediated, IL-12-driven Th1-cell response also induces granuloma assembly in parasitized liver (17, 21, 28) and regulates the leishmanicidal activity of Sb (19). Therefore, seeking differences between IL-12p40–/– and p35–/– mice and between IL-18–/– and WT mice, we examined histologic reactions (Fig. 4) and Sb-induced parasite killing (Table 1).


Figure 4
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  		FIG. 4. Photomicrographs of liver sections from L. donovani-infected mice. Arrows indicate infected foci. WT BALB/c mice (A) generate granulomas at parasitized foci by week 4, while IL-12p35–/– (B) and p40–/– (C) mice show little inflammatory response at week 8 in heavily infected Kupffer cells which have coalesced into masses of intracellular parasites. At week 2, granulomas are well established in C57BL/6 WT mice (D) but nearly absent at parasitized foci in IL-18–/– mice (E); however, by week 8, IL-18–/– mice develop mature-appearing granulomas (F). Original magnification, x400.

 

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  		TABLE 1. Leishmanicidal responses to chemotherapya

 
Granuloma assembly in the liver correlated with outcome of infection: (i) BALB/c and C57BL/6 WT mice generated numerous mature-appearing granulomas by weeks 2 through 4 at >90% of parasitized foci, (ii) few granulomas developed in either IL-12p35–/– or p40–/– mice by weeks 8 through 12, and (iii) while initially suppressed at week 2, IL-18–/– animals expressed a granulomatous response by week 4 which was well developed by week 8 (Fig. 4). The tissue responses in IL-12p35–/– and p40–/– mice were not discernibly different. In both, heavily infected foci showed few recruited mononuclear cells, nearly indistinguishable from the absent inflammatory reaction in livers of BALB/c IFN-{gamma}–/– mice 8 to 12 weeks after infection (not shown) (21). Similarly, and also akin to IFN-{gamma}–/– mice (19), the parasite-killing response to Sb chemotherapy was comparably impaired in IL-12p40–/– and p35–/– mice (Table 1). In contrast, IL-18–/– animals responded normally to treatment, likely reflecting intact production of IFN-{gamma}, which regulates the Sb effect (19).

While IL-12p40–/– mice are known to be susceptible to L. donovani (28, 36), this and a previous study with IL-12p35–/– mice (18) make it clear that the central position occupied by IL-12 in acquired resistance to L. donovani cannot be compensated for by other cytokines, including IL-18. At the same time, however, our results also suggest that the spectrum of cytokines which exert IL-12-independent regulatory roles in visceral infection (5, 10, 19, 20, 35) can be expanded to include IL-18 and probably IL-23. Since animals deficient in IL-23 alone (e.g., p19–/– mice) (8, 25) have not yet been tested, a role for IL-23 in the absence of IL-12 can only be inferred from the data derived in IL-12p40–/– mice. In this setting, IL-23 exerts an apparent antileishmanial effect in late-stage visceral infection. Since p35–/– mice, deficient in IL-12 alone, showed near-absent IFN-{gamma} and granuloma responses, testing in p19–/– mice will be important to better clarify IL-23's role and mechanism which may involve induction of cytokines other than IFN-{gamma} (8). In contrast, the IL-18-dependent antileishmanial mechanism identified here primarily acted early in infection before becoming dispensable, and influenced early granuloma assembly but not IFN-{gamma} secretion. Eventual control of infection and intact IFN-{gamma} have also been reported in cutaneous Leishmania major infection in these same IL-18–/– mice (12).

IL-18 and IL-23 are pleiotropic cytokines (4, 9, 13, 25, 31); thus, multiple mechanisms may underlie their effects. In addition, the recent demonstration that IL-12p40–/–/IL-18–/– mice, deficient in IL-12, IL-23, and IL-18, retain IFN-{gamma}-dependent intracellular antimicrobial activity (6) also suggests the presence of still other mechanisms for IFN-{gamma} induction and macrophage activation.


   ACKNOWLEDGMENTS
 
This work was supported by NIH grants AI 16369 (H.W.M.) and AI 45899 (X.M.).

C. Biron generously provided IL-18–/– breeders, mice originally developed by S. Akira and K. Takeda.


   FOOTNOTES
 
* Corresponding author. Mailing address: Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021. Phone: (212) 746-6330. Fax: (212) 746-6332. E-mail: hwmurray{at}med.cornell.edu. Back

Editor: W. A. Petri, Jr.


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Infection and Immunity, July 2006, p. 4370-4374, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.00422-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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