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. 2011 Apr 15;186(8):4895-904.
doi: 10.4049/jimmunol.1000594. Epub 2011 Mar 11.

Decreased leukocyte accumulation and delayed Bordetella pertussis clearance in IL-6-/- mice

Xuqing Zhang  1 , Tania Goel, Laura L Goodfield, Sarah J Muse, Eric T Harvill
Affiliations

Decreased leukocyte accumulation and delayed Bordetella pertussis clearance in IL-6-/- mice

Xuqing Zhang et al. J Immunol. .

Abstract

IL-6, a pleiotropic cytokine primarily produced by the innate immune system, has been implicated in the development of acquired immune responses, though its roles are largely undefined and may vary in the context of different diseases. Using a murine model of infection, we established that IL-6 influences the adaptive immune responses against the endemic human respiratory pathogen Bordetella pertussis. IL-6 was induced in the lungs of C57BL/6 mice by B. pertussis. IL-6(-/-) mice showed a protracted infectious course and were less efficiently protected by B. pertussis vaccination than wild-type mice. Abs from IL-6(-/-) mice, though lower in titer, efficiently reduced B. pertussis numbers in IL-6-sufficient mice. Pulmonary leukocyte recruitment and splenic or pulmonary T cell cytokine responses to B. pertussis, including Th1 and Th17 cytokine production, were lower in IL-6(-/-) mice than in wild-type mice. Adoptive transfer of immune wild-type CD4(+) cells ameliorated the defect of IL-6(-/-) mice in the control of B. pertussis numbers. Together, these results reveal the dysregulation of multiple aspects of adaptive immune responses in B. pertussis-infected IL-6(-/-) mice and suggest that IL-6 is involved in regulating Ab generation, pulmonary leukocyte accumulation, and T cell cytokine production in response to B. pertussis as well as the generation of effective vaccine-induced immunity against this pathogen.

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Figures

Figure 1
Figure 1
B. pertussis induces IL-6 in vitro and in vivo. A, RAW 264.7 cells were incubated with media alone (white bars) or media with live B. pertussis at an MOI of 1 (dashed bars) or 10 (black bars) for the indicated time. IL-6 concentration in culture supernatants of four similarly treated wells is shown as mean ± SE. **p ≤ 0.01 comparing MOI of 1 and 10, ##p ≤ 0.01 compared with media-treated wells. B, Groups of three to four C57BL/6 mice were inoculated with B. pertussis and sacrificed at the indicated time points. IL-6 concentration in the lungs of each group of mice is expressed as mean ± SE. *p ≤ 0.05, **p ≤ 0.01 compared with levels at 0 h.
Figure 2
Figure 2
Delayed clearance of B. pertussis in IL-6−/− mice. Groups of three to four C57BL/6 (solid line with diamonds) and IL-6−/− (dashed line with squares) mice were inoculated with B. pertussis and sacrificed on the indicated days postinoculation. Bacterial loads are expressed as mean Log10CFU ± SE. The dashed line indicates the limit of detection. *p ≤ 0.05, **p ≤ 0.01 compared with numbers in C57BL/6 mice at the same time point.
Figure 3
Figure 3
IL-6 contributes to the generation of efficient vaccine-induced immunity against B. pertussis. Groups of four naive or vaccinated C57BL/6 (black bars) or IL-6−/− (white bars) mice were challenged with B. pertussis and sacrificed on day 3 postchallenge. Bacterial loads are expressed as mean Log10CFU ± SE. The dashed line indicates the limit of detection. **p ≤ 0.01. ND, undetectable bacterial number.
Figure 4
Figure 4
Serum Abs from IL-6−/− mice are sufficient for Ab-mediated clearance of B. pertussis, despite lower titers. A, Serum was collected from groups of four B. pertussis-inoculated C57BL/6 (solid line with diamonds) or IL-6−/− (dashed line with squares) mice on days 28, 49, 77, and 108 postinoculation. B. pertussis-specific Ab titers are expressed as mean Log10Titer ± SE. The dashed line indicates the limit of detection. *p ≤ 0.05, **p ≤ 0.01 compared with titers in C57BL/6 mice at the same time point. ND, undetectable titer. B, Groups of three to four μMT mice were adoptively transferred naive serum (NS, dashed bars) or immune serum (IS) from C57BL/6 (black bars) or IL-6−/− mice (white bars) right before B. pertussis inoculation. Mice were sacrificed 14 d postinoculation. Bacterial numbers in the lung are expressed as mean Log10CFU ± SE. The dashed line indicates the limit of detection. *p ≤ 0.05. C, Group of three to four C57BL/6 (black bars) and IL-6−/− (white bars) mice were adoptively transferred naive serum (NS) or immune serum (IS) from C57BL/6 mice at the time of B. pertussis inoculation. These mice and the control mice not given any serum Abs (none) were sacrificed on days 14 or 21 postinoculation. Bacterial numbers in the lung are expressed as mean Log10CFU ± SE. The dashed line indicates the limit of detection. #p ≤ 0.05, ##p ≤ 0.01 compared with similarly treated wild-type mice; *p ≤ 0.05, **p ≤ 0.01 compared with the naive serum treated group.
Figure 5
Figure 5
IL-6 contributes to the recruitment of leukocytes into B. pertussis-infected lungs. A, Total leukocyte, CD4+ T cell, and Ly6G+ neutrophil numbers in the lungs of groups of four C57BL/6 (black bars) and IL-6−/− (white bars) mice on day 28 post B. pertussis inoculation are expressed as mean ± SE. Fold induction (relative to naive mice) of the chemokines KC, LIX, MIP-2 (B), CCL2, or CXCL10 (C) mRNA levels in the lungs of groups of three to four C57BL/6 (black bars) and IL-6−/− (white bars) mice on the indicated days post B. pertussis inoculation are expressed as mean ± SE. *p ≤ 0.05, **p ≤ 0.01.
Figure 6
Figure 6
Splenic cytokine production is dampened in B. pertussis-inoculated IL-6−/− mice. Splenocytes from groups of three to four C57BL/6 (black bars) and IL-6−/− (white bars) mice sacrificed on the indicated days post B. pertussis-inoculation were exposed to heat-killed B. pertussis for 3 d. The IFN- γ, IL-10, IL-4, IL-5, GM-CSF (A) or IL-17 (B) concentrations in the culture supernatant are expressed as mean ± SE. C, Numbers of IFN- γ –, IL-10–, or IL-17–producing splenic leukocytes from groups of three to four naive or B. pertussis-inoculated C57BL/6 (black bars) or IL-6−/− (white bars) mice were determined by ELISPOT and expressed as mean ± SE. D, Splenocytes from groups of three to four C57BL/6 and IL-6−/− mice sacrificed on day 14 post B. pertussis inoculation were exposed to heat-killed B. pertussis for 72 h. Percentage of IFN-γ + or IL-17+ cells were determined by intracellular cytokine staining and representative dot plots were shown. Live leukocytes were gated based on FSC and SSC. *p ≤ 0.05, **p ≤ 0.01.
Figure 7
Figure 7
Numbers and percentage of IFN- γ– or IL-17–producing lung leukocytes are reduced in B. pertussis-inoculated IL-6−/− mice. IFN-γ– (A) or IL-17–producing (B) leukocytes in the lungs of groups of three to four naive or B. pertussis-inoculated C57BL/6 (black bars) or IL-6−/− (white bars) mice were determined by ELISPOT and expressed as mean ± SE. Lung leukocytes from groups of three to four C57BL/6 and IL-6−/− mice sacrificed on day 14 post B. pertussis inoculation were stimulated with PMA and ionomycin for 4 h. Percentage of CD4+ IFN- γ +(C) or CD4+IL-17+ cells (D) were determined by intracellular cytokine staining, and representative dot plots were shown. Live leukocytes were gated based on FSC and SSC. *p ≤ 0.05. ND, undetectable numbers.
Figure 8
Figure 8
Adoptive transfer of splenocytes from immune wild-type mice reduces B. pertussis numbers in IL-6−/− mice. A total of 106 naive splenocytes or splenocytes collected from C57BL/6 mice on day 28 post B. pertussis inoculation (immune) that were enriched for CD4+ population were i.v. injected into groups of three to seven C57BL/6 (black bars) or IL-6−/− (white bars) mice 2 h prior to B. pertussis inoculation. Bacterial numbers in the lungs on day 14 postinoculation are expressed as mean Log10CFU ± SE. *p ≤ 0.05, **p ≤ 0.01.
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