GRO CHEMOKINES - A TRANSDUCTION, INTEGRATION, AND AMPLIFICATION MECHANISM IN ACUTE RENAL INFLAMMATION

We recently observed that cytokine-induced neutrophil chemoattractant (CINC), a GRO chemokine, contributes to neutrophil migration into the inflamed glomerulus in rat. Therefore, we sought to clarify how expres sion of the GRO chemokines, CINC and macrophage inflammatory protein-2 (MIP-2), is regulated in mesangial cells in vitro and the kidney in v ivo. Mesangial cells expressed both GRO chemokine mRNAs in response to mediators of acute renal inflammation [interleukin-1 beta (IL-1 beta) , tumor necrosis factor-alpha (TNF-alpha), and lipopolysaccharides (LP S)], but not chronic renal inflammation (transforming growth factor-be ta 1), with CINC mRNA expression predominating over MIP-2. The kinetic s of GRO chemokine mRNA expression in response to both IL-1 beta and T NF-alpha (but not LPS) parceled those defined for polymorphonuclear le ukocyte (PMN) migration during nephritis in vivo. IL-1 beta and TNF-al pha displayed nonparallel concentration-response relationships for GRO chemokine mRNA expression, and together were synergistic together rat her than additive. Expression of GRO chemokine mRNAs in response to bo th cytokine agonists, however, was inhibited by genistein, a tyrosine kinase inhibitor. GRO chemokine mRNAs were rapidly expressed in inflam ed glomeruli during immune complex glomerulonephritis with MIP-2 predo minating over CINC. Expression of both chemokines was substantially in hibited by complement, leukocyte, and PMN depletion. In sum, GRO chemo kines are expressed coordinately by mesangial cells and inflamed glome ruli and appear both to transduce the response to mediators of acute i nflammation into a chemotactic signal and to amplify this response bot h temporally and quantitatively. Moreover, chemokine expression in viv o appears to be a function of the integrated response of both intrinsi c glomerular cells and leukocytes, particularly PMNs.