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Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes.
J Immunol 1993; 151(12):6692-700JI

Abstract

Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes.

Authors+Show Affiliations

Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla 92093.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8258685

Citation

Geng, Y, et al. "Protein Tyrosine Kinase Activation Is Required for Lipopolysaccharide Induction of Cytokines in Human Blood Monocytes." Journal of Immunology (Baltimore, Md. : 1950), vol. 151, no. 12, 1993, pp. 6692-700.
Geng Y, Zhang B, Lotz M. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J Immunol. 1993;151(12):6692-700.
Geng, Y., Zhang, B., & Lotz, M. (1993). Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. Journal of Immunology (Baltimore, Md. : 1950), 151(12), pp. 6692-700.
Geng Y, Zhang B, Lotz M. Protein Tyrosine Kinase Activation Is Required for Lipopolysaccharide Induction of Cytokines in Human Blood Monocytes. J Immunol. 1993 Dec 15;151(12):6692-700. PubMed PMID: 8258685.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. AU - Geng,Y, AU - Zhang,B, AU - Lotz,M, PY - 1993/12/15/pubmed PY - 1993/12/15/medline PY - 1993/12/15/entrez SP - 6692 EP - 700 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 151 IS - 12 N2 - Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/8258685/Protein_tyrosine_kinase_activation_is_required_for_lipopolysaccharide_induction_of_cytokines_in_human_blood_monocytes_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=8258685 DB - PRIME DP - Unbound Medicine ER -