Gro chemokines: a transduction, integration, and amplification mechanism in acute renal inflammation. Wu, Xiaobo, Gregory J. Dolecki, James B. Lefkowith. Departments of Medicine and Molecular Biology and Pharmacology, Washington University School of Medicine, St.Louis, MO 63110
APStracts 2:0037F, 1995.
We recently observed that CINC (cytokine-induced neutrophil chemoattractant), a GRO chemokine, contributes to neutrophil migration into the inflamed glomerulus in rat. In consequence, we sought to clarify how expression of the GRO chemokines, CINC and MIP -2 (macrophage inflammatory protein-2)), is regulated in mesangial cells in vitro and the kidney in vivo. Mesangial cells expressed both GRO chemokine mRNAs in response to mediators of acute renal inflammation (IL-1[beta], TNF-[alpha], and LPS), but not chronic renal inflammation (TGF-[beta]1), with CINC mRNA expression predominating over MIP-2. The kinetics of GRO chemokine mRNA expression in response to both IL-1[beta] and TNF-[alpha] (but not LPS) paralleled those defined for PMN migration during nephritis in vivo. IL-1[beta] and TNF-[alpha] displayed non-parallel concentration-response relationships for GRO chemokine mRNA expression and together were synergistic together rather than additive. Expression of GRO chemokine mRNAs in response to both cytokine agonists, however, was inhibited by genistein, a tyrosine kinase inhibitor. GRO chemokine mRNAs were rapidly expressed in inflamed glomeruli during immune complex glomerulonephritis with MIP -2 predominating over CINC. Expression of both chemokines was substantially inhibited by complement, leukocyte and PMN depletion. In sum, GRO chemokines are expressed coordinately by mesangial cells and inflamed glomeruli, and appear both to transduce the response to mediators of acute inflammation into a chemotactic signal and to amplify this response both temporally and quantitatively. Moreover, chemokine expression in vivo appears to be a function of the integrated response of both intrinsic glomerular cells and leukocytes, particularly PMNs. 

Received 21 November 1994; accepted in final form 23 February
1995.
APS Manuscript Number F415-4.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 28 March 1995.