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Infect Immun. 1995 Jun; 63(6): 2262–2268.
PMCID: PMC173295

Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia.


We have produced interleukin-6 (IL-6)-deficient mice to examine, in vivo, the wide variety of biological activities attributed to this multifunctional cytokine. To investigate the role of IL-6 during infectious disease, IL-6-deficient mice were challenged with sublethal doses of Listeria monocytogenes, a facultative intracellular bacterium. While normal control animals were able to clear the infection, mutant animals exhibited a high mortality rate and showed uncontrolled replication of the bacteria in the spleen and liver at 2 and 3 days postinfection. Sections of infected tissues showed an increase in the number and severity of inflammatory foci. All aspects of this phenotype in the mutant animals were completely reverted upon administration of recombinant murine IL-6 (rIL-6). Various parameters of natural killer (NK) cell and macrophage function were unaffected in the challenge of the mutant animals. However, IL-6-deficient animals failed to mount peripheral blood neutrophilia in response to listeriosis, whereas control animals displayed a prominent neutrophilia in the blood at 24 and 48 h postinfection. Additionally, we analyzed the efficacy of rIL-6 in protecting animals devoid of lymphocytes or devoid of neutrophils during listeriosis. Administration of rIL-6 was protective to animals devoid of lymphocytes, suggesting that the rIL-6 protective effect was not mediated through lymphocytes. In contrast, control and mutant animals depleted of neutrophils were refractory to the rIL-6 protective effect. These data suggest that IL-6 is critical early during listeriosis, perhaps acting by stimulating neutrophils either directly or indirectly. Additionally, these data show a promising therapeutic potential for rIL-6 administration during opportunistic infection.

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Selected References

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  • Abrams JS, Roncarolo MG, Yssel H, Andersson U, Gleich GJ, Silver JE. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol Rev. 1992 Jun;127:5–24. [PubMed]
  • Borish L, Rosenbaum R, Albury L, Clark S. Activation of neutrophils by recombinant interleukin 6. Cell Immunol. 1989 Jul;121(2):280–289. [PubMed]
  • Buchmeier NA, Schreiber RD. Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7404–7408. [PMC free article] [PubMed]
  • Conlan JW, North RJ. Neutrophils are essential for early anti-Listeria defense in the liver, but not in the spleen or peritoneal cavity, as revealed by a granulocyte-depleting monoclonal antibody. J Exp Med. 1994 Jan 1;179(1):259–268. [PMC free article] [PubMed]
  • Czuprynski CJ, Brown JF. Recombinant murine interleukin-1 alpha enhancement of nonspecific antibacterial resistance. Infect Immun. 1987 Sep;55(9):2061–2065. [PMC free article] [PubMed]
  • Czuprynski CJ, Brown JF, Maroushek N, Wagner RD, Steinberg H. Administration of anti-granulocyte mAb RB6-8C5 impairs the resistance of mice to Listeria monocytogenes infection. J Immunol. 1994 Feb 15;152(4):1836–1846. [PubMed]
  • Czuprynski CJ, Henson PM, Campbell PA. Killing of Listeria monocytogenes by inflammatory neutrophils and mononuclear phagocytes from immune and nonimmune mice. J Leukoc Biol. 1984 Feb;35(2):193–208. [PubMed]
  • Dinarello CA. The endogenous pyrogens in host-defense interactions. Hosp Pract (Off Ed) 1989 Nov 15;24(11):111–passim. [PubMed]
  • Dunn PL, North RJ. Early gamma interferon production by natural killer cells is important in defense against murine listeriosis. Infect Immun. 1991 Sep;59(9):2892–2900. [PMC free article] [PubMed]
  • Handa K, Suzuki R, Matsui H, Shimizu Y, Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). II. IL 2-induced interferon gamma production. J Immunol. 1983 Feb;130(2):988–992. [PubMed]
  • Havell EA, Sehgal PB. Tumor necrosis factor-independent IL-6 production during murine listeriosis. J Immunol. 1991 Jan 15;146(2):756–761. [PubMed]
  • Heremans H, Dillen C, Put W, Van Damme J, Billiau A. Protective effect of anti-interleukin (IL)-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels. Eur J Immunol. 1992 Sep;22(9):2395–2401. [PubMed]
  • Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986 Nov 6;324(6092):73–76. [PubMed]
  • Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Köhler G. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994 Mar 24;368(6469):339–342. [PubMed]
  • Lanier LL, Le AM, Phillips JH, Warner NL, Babcock GF. Subpopulations of human natural killer cells defined by expression of the Leu-7 (HNK-1) and Leu-11 (NK-15) antigens. J Immunol. 1983 Oct;131(4):1789–1796. [PubMed]
  • Liu Z, Simpson RJ, Cheers C. Recombinant interleukin-6 protects mice against experimental bacterial infection. Infect Immun. 1992 Oct;60(10):4402–4406. [PMC free article] [PubMed]
  • Liu Z, Simpson RJ, Cheers C. Role of IL-6 in activation of T cells for acquired cellular resistance to Listeria monocytogenes. J Immunol. 1994 Jun 1;152(11):5375–5380. [PubMed]
  • MACKANESS GB. Cellular resistance to infection. J Exp Med. 1962 Sep 1;116:381–406. [PMC free article] [PubMed]
  • Nakane A, Minagawa T, Kato K. Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection. Infect Immun. 1988 Oct;56(10):2563–2569. [PMC free article] [PubMed]
  • Pamer EG, Harty JT, Bevan MJ. Precise prediction of a dominant class I MHC-restricted epitope of Listeria monocytogenes. Nature. 1991 Oct 31;353(6347):852–855. [PMC free article] [PubMed]
  • Pfeffer K, Matsuyama T, Kündig TM, Wakeham A, Kishihara K, Shahinian A, Wiegmann K, Ohashi PS, Krönke M, Mak TW. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993 May 7;73(3):457–467. [PubMed]
  • Rogers HW, Sheehan KC, Brunt LM, Dower SK, Unanue ER, Schreiber RD. Interleukin 1 participates in the development of anti-Listeria responses in normal and SCID mice. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1011–1015. [PMC free article] [PubMed]
  • Rogers HW, Tripp CS, Schreiber RD, Unanue ER. Endogenous IL-1 is required for neutrophil recruitment and macrophage activation during murine listeriosis. J Immunol. 1994 Sep 1;153(5):2093–2101. [PubMed]
  • Rogers HW, Unanue ER. Neutrophils are involved in acute, nonspecific resistance to Listeria monocytogenes in mice. Infect Immun. 1993 Dec;61(12):5090–5096. [PMC free article] [PubMed]
  • Rothe G, Kellermann W, Valet G. Flow cytometric parameters of neutrophil function as early indicators of sepsis- or trauma-related pulmonary or cardiovascular organ failure. J Lab Clin Med. 1990 Jan;115(1):52–61. [PubMed]
  • Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. [PubMed]
  • Starnes HF, Jr, Pearce MK, Tewari A, Yim JH, Zou JC, Abrams JS. Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol. 1990 Dec 15;145(12):4185–4191. [PubMed]
  • Suzuki Y, Yang Q, Conley FK, Abrams JS, Remington JS. Antibody against interleukin-6 reduces inflammation and numbers of cysts in brains of mice with toxoplasmic encephalitis. Infect Immun. 1994 Jul;62(7):2773–2778. [PMC free article] [PubMed]
  • Tanabe O, Akira S, Kamiya T, Wong GG, Hirano T, Kishimoto T. Genomic structure of the murine IL-6 gene. High degree conservation of potential regulatory sequences between mouse and human. J Immunol. 1988 Dec 1;141(11):3875–3881. [PubMed]
  • Tepper RI, Coffman RL, Leder P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science. 1992 Jul 24;257(5069):548–551. [PubMed]
  • Ulich TR, del Castillo J, Guo KZ. In vivo hematologic effects of recombinant interleukin-6 on hematopoiesis and circulating numbers of RBCs and WBCs. Blood. 1989 Jan;73(1):108–110. [PubMed]
  • Wolvekamp MC, Marquet RL. Interleukin-6: historical background, genetics and biological significance. Immunol Lett. 1990 Mar-Apr;24(1):1–9. [PubMed]

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