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Characteristics of soluble tumour-derived proteins that inhibit natural killer activity
M K Heiskala1, U H Stenman, E Koivunen
1Department of Obstetrics and Gynaecology, University of Helsinki, Finland.
Abstract:
We have previously shown that various benign and malignant natural killer (NK)-resistant monolayer cells inhibit endogenous human NK activity, probably by reducing the secretion of cytotoxic factors from the effector cells. The nature of the molecules responsible for the inhibition has been unclear. In this study we show that phosphate-buffered saline (PBS) extracts of ovarian cystadenocarcinoma tissue and normal uterine smooth muscle strongly inhibit NK activity. Fractionation of tumour extracts by gel chromatography revealed major inhibitory activity in the Mr range 160,000-180,000, and other weaker inhibiting activities in the Mr ranges 50,000-70,000 and 20,000. The active material of Mr range 160,000-180,000 was adsorbed on anion exchange chromatography column at neutral pH and physiologic NaCl concentration, and it was eluted by 0.31-0.34 M NaCl. The inhibitory molecule was sensitive to proteolysis. No relation of this compound to immunoglobulins or trypsin and urokinase inhibitors was detected. The unfractionated extract inhibited NK activity apparently by the same mechanism as the monolayer target cells, i.e. by reducing the secretory capacity of effector cells. The data strongly suggest that the NK-inhibiting compounds described in this work are involved in the inactivation of NK cells by intact monolayer cells.
Insights
Tumor extracts contain molecules that inhibit natural killer (NK) cell activity by reducing their cytotoxic factor secretion. These NK-inhibiting compounds may play a role in how tumor cells inactivate NK cells.
Area of Science:
- Immunology
- Biochemistry
Background:
- Previous studies indicated that natural killer (NK)-resistant cells can inhibit endogenous human NK activity.
- The specific molecules responsible for this inhibition remained unidentified.
Purpose of the Study:
- To identify the molecules responsible for the inhibition of natural killer (NK) cell activity by ovarian cystadenocarcinoma and normal uterine smooth muscle extracts.
Main Methods:
- Phosphate-buffered saline (PBS) extracts of tumor and muscle tissues were prepared.
- Gel chromatography and anion exchange chromatography were used for fractionation.
- Inhibitory activity was assessed by measuring NK cell activity.
- Sensitivity to proteolysis was tested.
Main Results:
- Tumor and muscle extracts strongly inhibited NK activity.
- Major inhibitory activity was found in the Mr range of 160,000-180,000, with weaker activities at 50,000-70,000 and 20,000.
- The primary inhibitory molecule was sensitive to proteolysis and eluted at 0.31-0.34 M NaCl.
- No relation to immunoglobulins or known inhibitors was detected.
Conclusions:
- The study identified NK-inhibiting compounds in ovarian tumor and uterine muscle extracts.
- These compounds likely function by reducing the secretion of cytotoxic factors from NK cells.
- The findings suggest these molecules are involved in the inactivation of NK cells by intact tumor cells.