Interleukin-4 suppresses plasminogen activator inhibitor-2 formation in stimulated human monocytes

Abstract

Using a specific enzyme-linked immunosorbent assay, plasminogen activator inhibitor-2 (PAI-2) was quantitated in cultures of human monocytes. Lipopolysaccharide (LPS) increased both extracellular and cell-associated PAI-2 levels, as well as PAI-2 mRNA measured by Northern analysis. Both the lymphokine, interleukin-4 (IL-4) (greater than or equal to 10 pmol/L), and the glucocorticoid, dexamethasone (100 nmol/L), inhibited PAI-2 formation and PAI-2 mRNA induction. Another lymphokine, interferon-gamma (IFN-gamma) (100 U/mL), as for IL-4 alone, did not stimulate PAI-2 formation; however, in contrast to IL-4, IFN- gamma did not reverse the LPS effect but could potentiate it. The suppression of PAI-2 formation by IL-4 and glucocorticoid in stimulated human monocytes extends the list of monocyte products whose synthesis can be downregulated in these cells by the two agents. The findings could have relevance to the control by monocytes/macrophages of connective tissue resorption, including that of fibrin, at sites of inflammation.

SerpinB2 inhibits migration and promotes a resolution phase signature in large peritoneal macrophages

“…Also identified by the IPA USR (Fig. S1b) was (i) HMGB1, the prototypical endogenous danger molecule 59 , with a positive z-score, consistent with up-regulation of SerpinB2 by pathogens and endogenous danger signals 20,60 and (ii) the glucocorticoid receptor (NR3C1) with a negative z-score, consistent with down-regulation of SerpinB2 by glucocorticoids 61 .…”

Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis

“…Macrophage tPA activity could be critical in determining the degree of fibrin deposition in rheumatoid synovial tissue. Monocyte/macrophages can make PAI‐1 and PAI‐2 (63–65). The production of both PAI‐1 and PAI‐2 in human monocytes is up‐regulated by GM‐CSF and M‐CSF (66); however, independent expression was noted in response to lipopolysaccharide, TGFβ, and IL‐4, and to a glucocorticoid (64, 65).…”

Fibrin-mediated Protection Against Infection-stimulated Immunopathology

“…Similar results to those shown were replicated in two (A) or more (B-E) independent experiments. 805 Johnson et al Brief Definitive Report cellular expression of procoagulant molecules (26)(27)(28), thereby potentially amplifying fibrin production.…”

“…Remarkably, fibrin does not simply protect against vascular damage caused directly by the infectious agent, but rather, protects against hemorrhage evoked by IFN-␥, a critical mediator of type 1 immunity. Notably, IFN-␥ also stimulates expression of genes that favor and/or stabilize fibrin deposition (26)(27)(28), suggesting that type 1 immunity may have evolved means to locally up-regulate coagulant activity, thereby preemptively protecting against its own destructive power.…”