Role of the mevalonate pathway of isoprenoid synthesis in IL-8 generation by activated monocytic cells

Abstract

The highly regulated enzyme HMG-CoA reductase generates mevalonate, the precursor of a complex series of isoprenoids that posttranslationally modify (isoprenylate) certain proteins (e.g., the low-molecular-weight GTP-binding proteins) or that are incorporated into cholesterol and other end products. We recently reported that isoprenoids are required for NADPH oxidase activity in granulocytes via LMW GTP-binding protein isoprenylation. In this study, we evaluated the effects of isoprenoid depletion on the expression of proinflammatory genes in human monocytic THP-1 cells. We selected conditions under which pretreatment for 24 h with isoprenoid synthesis inhibitors (HMG-CoA reductase inhibitor lovastatin or compactin at 10 microM) did not compromise cell viability but markedly suppressed H2O2 generation. Under these conditions interleukin-8 (IL-8) production was attenuated (by 50-90%) in response to lipopolysaccharide, granulocyte-macrophage colony-stimulating factor, and phorbol myristate acetate. Coincubation of reductase inhibitor-treated cells with mevalonate prevented the attenuation of IL-8 production by reductase inhibitors. The effects of isoprenoid depletion on cytokine production were selective: IL-1 beta generation was not inhibited but the production of IL-6 and IL-8 was concomitantly suppressed. IL-8 induction was suppressed at least in part through attenuation of the increase in mRNA in stimulated cells. We conclude that isoprenoid generation through the mevalonate pathway is a requirement for IL-8 induction by activated monocytic cells in vitro. Isoprenylation inhibitors have the potential to alter monocyte proinflammatory function.

Inhibition of Monocyte Chemotactic Protein-1 Synthesis by Statins

“…The results obtained in this study indicated that the effective dose of statins depends on the type of target cells (Kluft et al, 1999;van Vliet et al, 1996), and was in accordance with previous data showing that cytokine production (IL-6 and IL-8) in the myeloid leukemia THP-1 cell line was inhibited at lovastatin and fluvastatin concentrations of 10 M (Ikeda and Shimada, 1999;Terkeltaub et al, 1994), whereas MCP-1 production by human fetal mesangial cells, vascular smooth muscle cells, or U937 cells (Kim et al, 1995;Ortego et al, 1999) was inhibited at a concentration of 1 M.…”

“…Experimental evidence supports this, by showing that the in vitro inhibition of mevalonate synthesis induced apoptosis of rat vascular smooth muscle cells and decreased the proliferation of rat mesangial cells (O'Donnell et al, 1993). Moreover, the inhibition of isoprenoid synthesis reduced the production of interleukin (IL)-8 and IL-6 in THP-1 cells, a myeloid leukemia cell line with a mature monocyte phenotype, treated with lipopolysaccharide (LPS) or phorbol myristate acetate (Ikeda and Shimada, 1999;Terkeltaub et al, 1994). The production and expression of monocyte chemotactic protein-1 (MCP-1) in response to fetal bovine serum was also inhibited by lovastatin in fetal human mesangial cells (Kim et al, 1995) and in vivo in nephrotic rats (Park et al, 1998).…”

Simvastatin Inhibits Airway Hyperreactivity

“…Furthermore, the observed simvastatin inhibition of airway eosinophilia ( Figure 1B) could also be due to broader systemic effects on T cells with subsequent inhibition of eosinophilic chemotaxis and transmigration (31,32). Statins also modulate monocyte-macrophage function and inflammatory responses (33,34), consistent with our finding of reduced BALF macrophage counts ( Figure 1D). Peripheral blood mononuclear cells from patients with asthma display reduced chemokine and cytokine production after fluvastatin treatment (35), antiinflammatory effects that may be mediated via GGPP depletion (Scheme 1) (36).…”

In Vivo Anti-Inflammatory Effect of Statins Is Mediated by Nonsterol Mevalonate Products

“…13 Inhibition of HMG-CoA reductase activity in monocytes 14 and rat mesangial cell lines 15,16 treated with lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), and phorbol myristate acetate, reduced the production of interleukin (IL)-8, IL-6, and monocyte chemotactic protein-1 (MCP-1), all factors involved in plaque formation and stabilization. 12 A reduction of glomerular macrophage influx in nephrotic rats after lovastatin treatment, due to reduced expression of MCP-1, was reported, 17 suggesting that the inhibition of mevalonate synthesis may influence leukocyte recruitment at the infection site.…”