Cytokines and Neutrophils in the Urinary Tract Mucosa

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.