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 vi vo, the wide variety of biological activities attributed to this multi functional cytokine. To investigate the role of IL-6 during infectious disease, IL-6-deficient mice were challenged with sublethal doses of Listeria monocgtogenes, a facultative intracellular bacterium. While n ormal control animals were able to clear the infection, mutant animals exhibited a high mortality rate and showed uncontrolled replication o f the bacteria in the spleen and liver at 2 and 3 days postinfection. Sections of infected tissues showed an increase in the number and seve rity of inflammatory foci. All aspects of this phenotype in the mutant animals were completely reverted upon administration of recombinant m urine IL-6 (rIL-6). Various parameters of natural killer (NK) cell and macrophage function were unaffected in the challenge of the mutant an imals. However, IL-6 deficient animals failed to mount peripheral bloo d neutrophilia in response to listeriosis, whereas control animals dis played a prominent neutrophilia in the blood at 24 and 38 h postinfect ion. Additionally, we analyzed the efficacy of rIL-6 in protecting ani mals devoid of lymphocytes or devoid of neutrophils during listeriosis . Administration of rIL-6 was protective to animals devoid of lymphocy tes, suggesting that the rIL-6 protective effect was not mediated thro ugh lymphocytes. In contrast, control and mutant animals depleted of n eutrophils 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. Additionall y, these data show a promising therapeutic potential for rIL-6 adminis tration during opportunistic infection.