NEUTRALIZATION OF IL-10 INCREASES SURVIVAL IN A MURINE MODEL OF KLEBSIELLA PNEUMONIA

Effective host defense against bacterial infection is dependent upon t he vigorous recruitment and activation of neutrophils and macrophages. We hypothesized that IL-10 is produced in the setting of bacterial pn eumonia, and this cytokine may attenuate host defense by inhibiting th e expression of important activating and chemotatic cytokines. CD-1 mi ce were challenged with either 30 mu l of saline or saline containing 10(3) CFUs of Klebsiella pneumoniae intratracheally (i.t.) and lungs w ere harvested at 8, 24, and 48 h. The i.t, inoculation with K. pneumon iae resulted in a 13-, 14-, and 8-fold increase in lung homogenate TNF , macrophage inflammatory protein-2 (MIP-2), and macrophage inflammato ry protein-1 alpha (MIP-1 alpha) levels, respectively, as compared wit h control animals. In addition, we observed an increase in IL-10 mRNA and protein levels in lung homogenates, maximal at 48 h postinoculatio n. To establish the biologic relevance of IL-10 in Klebsiella pneumoni a, we passively immunized CD-1 mice with 0.5 ml of rabbit anti-murine IL-10 serum or preimmune serum i.p. 2 h before i.t. administration of K. pneumoniae. Treatment of animals with anti-IL-10 serum resulted in increased Ievels of TNF, MIP-2, and MIP-1 alpha, respectively, with in lung homogenates at 24 and 48 h, as compared with preimmune-treated a nimals. Furthermore, neutralization of IL-10 resulted in a significant decrease in K. pneumoniae CFU in both lung homogenates and plasma har vested at 48 h, as well as a significant increase in survival in these animals. Our studies indicate that 1) IL-10 is produced during Klebsi ella pneumonia; and 2) inhibition of IL-10 bioactivity in vivo results in enhanced bacterial clearance, increased expression of proinflammat ory cytokines, and prolonged survival.