Comparison of MMP‐2 and MMP‐9 secretion from T helper 0, 1 and 2 lymphocytes alone and in coculture with macrophages

Abstract

Summary Metalloproteinases (MMPs) participate in extracellular matrix remodelling and regulatory signalling during chronic inflammatory states such as atherosclerosis formation. However, the sources and mediators of MMP upregulation need clarification. We investigated whether proinflammatory mouse T helper type 1 (Th1) lymphocytes are more active in MMP secretion than naïve Th0 or anti‐inflammatory Th2 phenotypes, in the absence of specific antigenic stimulation, under baseline conditions and after contact with irradiated macrophages. We also compared the effect of Th0, Th1 or Th2 lymphocyte‐conditioned medium and irradiated lymphocytes on MMP production from macrophages. Finally, we investigated whether CD40–CD40 ligand (CD40L) interactions were involved in T‐cell‐stimulated MMP secretion from macrophages. Under baseline conditions, MMP‐2 messenger RNA (mRNA) and protein levels were greater in Th1 than Th0 or Th2 lymphocytes; MMP‐9 mRNA, but not protein, was also upregulated. In the presence of irradiated macrophages MMP‐2 and MMP‐9 production from Th1 and Th2 was greater than from Th0 lymphocytes. Conditioned media from Th1 but not Th0 or Th2 cells increased MMP‐9 secretion from macrophages. Irradiated Th1 lymphocytes stimulated both MMP‐2 and MMP‐9 secretion from macrophages more than irradiated Th2 or Th0 cells; this activation was independent of CD40–CD40L interaction. These findings demonstrate for the first time greater MMP secretion by Th1 than Th2 or Th0 lymphocytes and their greater ability to upregulate macrophage MMP secretion in the absence of specific antigenic stimulation. These mechanisms could promote matrix turnover in inflammatory states and, for example, promote atherosclerotic plaque rupture.

Metalloproteinase Expression in Monocytes and Macrophages and its Relationship to Atherosclerotic Plaque Instability

“…Further upregulation of MMP-9 expression by LPS in human macrophages is only modest 47,61,63 or even absent 57 ; CD40L and ox-LDL are also ineffective. 51,59,67,68 MMP-9 expression is not upregulated in rabbit in vivo generated foam cells compared with nonfoamy macrophages. 51 Moreover human macrophage and rabbit foam cell MMP-9 expression is not affected by adenovirus-mediated overexpression of the inhibitory subunit of NF-B, IB␣.…”

1α,25‐dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection

“…14 Our experiments confirm this previous observation in MN and show for the first time that 1a,25(OH) 2 D 3 also regulates MMP-7 and MMP-10 expression in MN under basal conditions and/or during M. tuberculosis infection. As previous studies have suggested that an interaction between T cells and MN/macrophages enhances MMP expression by both cell populations 11,[22][23][24][25] we also investigated the effects of 1a,25(OH) 2 D 3 on MMP regulation in a mixed population of adherent and non-adherent PBMC. Our observation that each MMP analysed had higher constitutive expression in PBMC than in MN led us to investigate the influence of 1a,25(OH) 2 D 3 and M. tuberculosis on MMP secretion and activity in PBMC.…”

Soluble CD40 Ligand Promotes Macrophage Foam Cell Formation in the Etiology of Atherosclerosis

“…CD40L can stimulate endothelial cells to express adhesion molecules that accelerate the adhesion of macrophages to endothelial cells, which are responsible for inflammation and the initiation of atherosclerosis [16,17,18]. Furthermore, CD40L induces matrix metalloproteinase overexpression, which promotes atherosclerotic plaque rupture [19]. …”