Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-α and IL-1β production by human monocytes

Lior Shapira, Shogo Takashiba, Catherine Champagne, Salomon Amar, Thomas E. Van Dyke

Research output: Contribution to journalArticle

214 Citations (Scopus)

Abstract

Bacterial LPS stimulates human monocytes to secrete inflammatory cytokines, which are involved in several disease processes. However, the mechanism of LPS activation of cytokine expression and secretion is not completely understood. In this study, we investigated the signal transduction pathways involved in LPS-stimulated TNF-α and IL-1β secretion. TNF-α and IL-1β secretion were completely blocked by protein kinase C (PKC) and cyclic nucleotide-dependent protein kinase inhibitor, H-7, but were not affected by H-89, a specific cyclic nucleotide-dependent protein kinase inhibitor. In addition, LPS was found to induce activation of PKC, reaching maximal activity at 30 min and returning to unstimulated levels after 60 min. LPS stimulation only slightly increased intracellular levels of diacylglycerol, the natural activator of PKC, and pretreatment of monocytes with the diacylglycerol-kinase inhibitor, R59022, did not affect LPS-stimulated TNF- α secretion. LPS-induced PKC activation was found not to be affected by blocking of the LPS receptor, CD14, with mAb or by inhibition of protein tyrosine kinase with herbimycin A. However, these agents suppressed LPS- induced TNF-α secretion and TNF-α mRNA accumulation. The results suggest that TNF-α and IL-1β secretion after LPS stimulation of human monocytes requires the activation of protein tyrosine kinase and PKC, upstream to the activation of gene transcription. The activation of PKC by LPS is probably mediated by a diacylglycerol-independent pathway.

Original languageEnglish
Pages (from-to)1818-1824
Number of pages7
JournalJournal of Immunology
Volume153
Issue number4
Publication statusPublished - Aug 15 1994
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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