CYTOKINE-INDUCED NEUTROPHIL CHEMOATTRACTANT MEDIATES NEUTROPHIL INFLUX IN IMMUNE-COMPLEX GLOMERULONEPHRITIS IN RAT

Chemokines are a family of cytokines whose participation in inflammati on in vivo remains to be established. Using the rat model of anti-glom erular basement membrane (GBM) nephritis, we found that mRNA for the c hemokine CINC (cytokine-induced neutrophil chemoattractant) was induce d in the kidney, and the corresponding protein was elaborated by isola ted inflamed glomeruli. Production of CINC by glomeruli was unaffected by complement- or leukocyte-depletion prior to disease induction. Cyt okines which induce CINC expression in renal cells (TNF-alpha and IL-1 beta) were also expressed in the kidney during glomerular inflammatio n. TNF-alpha production, unlike CINC, was complement and leukocyte dep endent. In vivo administration of anti-CINC, but not anti-human IL-8, IgG selectively attenuated the influx of PMNs into the glomerulus and commensurately diminished proteinuria. The participation of CINC was n ot tissue-specific: anti-CINC IgG also diminished the influx of PMNs i n dermal immune complex inflammation. In sum, we propose that glomerul ar immune complex deposition/complement activation leads to cytokine p roduction which results in CINC expression by endogenous glomerular ce lls. The CINC produced plays a contributory role in the influx of PMNs into the glomerulus in the context of the activation of other inflamm atory mediators. These results suggest a potential role for CINC homol ogues, IL-8 and the GRO family of chemokines, in human immune complex- mediated disease.