Cytokines and Neutrophils in the Urinary Tract Mucosa

Abstract: This study investigated the urinary tract cytokine reponse to infection and the role of chemokines for neutrophil recruitment to the urinary tract. The results suggest that 1) IL-8 and TGFb are consitutively produced by uroepithelial cells in vivo, and that uroepithelial cells are stimulated to produce IL-1b and IL-6 by uropathogenic Escherichia coli. 2) MIP-2 (mouse IL-8 homologue) plays an important role in directing neutrophils to infected areas. MIP-2 concentrations showed a correlation to urine neutrophil numbers following experimental UTI in C3H/HeN mice. Anti-MIP-2 antibodies blocked neutrophil migration across the epithelium, resulting in neutrophil accumulation in the sub-epithelial space. 3) The role of neutrophils for bacterial clearance from the urinary tract was studied in C3H/HeN and C3H/HeJ mice. C3H/HeJ mice had a poor neutrophil response and were highly susceptible to infection. Blocking of neutrophil recruitment in C3H/HeN mice with anti-neutrophil antibody impaired bacterial clearance resulting in increase bacterial numbers, comparable to the C3H/HeJ mice. C3H/HeJ mice also showed a weak epithelial MIP-2 response. 4) Infection of IL-8 receptor knock out (mIL-8Rh KO) mice caused neutrophil accumulation in kidney and bladder tissues as the neutrophils failed to cross the epithelial barrier. The mIL-8Rh KO mice were susceptible to UTI and renal tissue damage was seen following long-term infection. These studies illustrate the importance of epithelial chemokines and chemokine receptors for neutrophil recruitment to the mucosa and for resistance to infection.