GRO chemokines: A transduction, integration, and amplification mechanism in acute renal inflammation

X. Wu, G. J. Dolecki, J. B. Lefkowith

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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 expression of the GRO chemokines, CINC and macrophage inflammatory protein-2 (MIP-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 [interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and lipopolysaccharides (LPS)], but not chronic renal inflammation (transforming growth factor-β1), with CINC mRNA expression predominating over MIP-2. The kinetics of GRO chemokine mRNA expression in response to both IL-1β and TNF-α (but not LPS) paralleled those defined for polymorphonuclear leukocyte (PMN) migration during nephritis in vivo. IL-1β and TNF-α displayed nonparallel 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.

Original languageEnglish
Pages (from-to)F248-F256
JournalAmerican Journal of Physiology - Renal Fluid and Electrolyte Physiology
Volume269
Issue number2 38-2
StatePublished - Jan 1 1995

Keywords

  • cytokine-induced neutrophil chemoattractant
  • glomerulonephritis
  • macrophage inflammatory protein-2
  • neutrophil

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