PMID: 8956972Nov 1, 1996Paper

Protein tyrosine kinase inhibition blocks granule exocytosis and cytolytic function of lymphokine-activated killer cells

Immunopharmacology
M J FrederickE A Grimm

Abstract

Short-term pretreatment of human lymphokine-activated killer cells (LAK) with the protein tyrosine kinase-specific inhibitor Herbimycin A (Herb A) blocked cytotoxic function against the NK-resistant (LAK-sensitive) tumor targets, SK-Mel-1 (human melanoma) and Daudi (human lymphoma). Greater than 50% inhibition of LAK activity was observed after a 2.5-h pretreatment with 0.125 microgram/ml (ca. 0.2 microM) Herb A. Inhibition of LAK occurred over a time interval in which LAK were not dependent upon IL-2 for maintenance of killing function, supporting the conclusion that the drug interfered with mobilization of cytotoxic function. Conjugate formation between LAK and tumor targets was unaffected by Herb A, indicating that inhibition was occurring at a post-binding step. Granule exocytosis as measured by BLT-esterase release was detected from LAK after coincubation with tumor targets, and was inhibited by Herb A pretreatment. The majority of LAK killing was dependent upon extracellular calcium, supporting the hypothesis that granule exocytosis rather than Fas ligand was the principal pathway leading to target cell death. The data suggest that protein tyrosine kinases play a pivotal role in LAK cytolytic function by regulating granul...Continue Reading

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Citations

Aug 1, 1997·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·M FrederickT K Yu
May 4, 2007·Toxicology and Applied Pharmacology·Alexander M RoweJohn B Barnett
Jun 8, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·T K YuE A Grimm
Dec 24, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Michael J Fuller, Allan J Zajac

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