Myeloid haemopoietic cells of patients with chronic granulomatous disease are relatively resistant to TNF.
Generation of superoxide may be a key step in the cytotoxicity mediated by tumour necrosis factor (TNF); cells that cannot produce oxygen radicals might be resistant to TNF. Myeloid haemopoietic cells from patients with chronic granulomatous disease (CGD) cannot produce a large burst of oxygen radicals; therefore we examined the ability of TNF to inhibit clonal growth of myeloid haemopoietic cells from patients and carriers with several types of CGD. Mononuclear light-density cells from the peripheral blood of 13 CGD patients (11 patients with defects of gp91-phox and two with p47-phox), five gp91-phox carriers and 10 normal volunteers were cultured with the appropriate growth factor and TNF in methylcellulose. As expected, TNF (0.001-100 ng/ml) inhibited colony formation of myeloid cells of normal volunteers in a dose-dependent manner. In contrast, clonal growth of myeloid cells of CGD patients was resistant to inhibition by TNF < or = 100 ng/ml. As expected, the effects of TNF on erythroid clonogenic cells, which are not capable of producing an oxygen burst, and the action of TGF-beta on clonal growth of myeloid cells, were similar in both the individuals with CGD and the normal volunteers. In X chromosome-linked female carriers of CGD (gp91-phox deficiency), TNF showed an intermediate cytotoxicity on clonal growth of myeloid cells, and analysis of NBT reduction demonstrated that the colonies derived from myeloid cells deficient in gp91-phox were resistant to TNF and those derived from the myeloid cells expressing gp91-phox were inhibited in their proliferation by TNF. This study shows for the first time that myeloid haemopoietic cells from patients with CGD are relatively resistant to the growth-inhibiting effects of high concentrations of TNF.
Sakashita
A
A
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine.
Curnutte
J T
JT
Koeffler
H P
HP
D001853:Bone Marrow / Q000473:pathology*; D002455:Cell Division; D004351:Drug Resistance; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology*; D006105:Granulomatous Disease, Chronic / Q000378:metabolism / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides