Heparin binding protein (CAP37) differentially modulates endotoxin-induced cytokine production.

BACKGROUND AND OBJECTIVE: CAP37, also known as heparin-binding protein (HBP), is neutrophil-derived protein with multifunctional properties that include monocyte chemotaxis and the enhancement of LPS-induced tumor necrosis factor (TNF-alpha), IL-1, IL-6, and PGE2production from isolated monocytes, which suggest a generalized effect on LPS-induced monocyte activation. In this study, we tested whether HBP amplifies the release of other LPS-responsive cytokines from isolated human monocytes. METHODS: Freshly isolated monocytes from 5 healthy donors were stimulated for 24 h with saline, LPS (10 ng/ml), HBP (10 microg/ml), or a combination of LPS + HBP. Cytokine levels in the supernate were measured with ELISA. ANOVA and Fisher's posthoc test were used to determine significance (p < 0.05). Differential display was used to assess cellular mRNA levels. RESULTS: HBP alone induced the production of IL-8, macrophage inhibitory protein MIP-1alpha, and TNF-alpha. HBP increased the LPS-induced production of IL-8, MIP-1alpha, TNF-alpha, IL-1beta, but HBP did not increase the significant LPS-induced release of IL-10, monocyte chemoattractant protein MCP-1, and IL- 12. Differential display demonstrated that HBP induced an mRNA pattern that was different from the mRNA pattern induced by saline, LPS, or HBP + LPS, indicating multiple and different gene activation. CONCLUSIONS: We conclude that HBP is not a general amplificator of LPS-induced monocyte activation but rather a molecule that targets the production of a distinct set of mediators including pro-inflammatory cytokines such as TNF-alpha and IL-1beta, but not the anti-inflammatory cytokine IL-10, nor IL-12 and MCP-1. The exact intracellular signaling pathways remain unknown but include mechanisms that alter gene transcription.