Recombinant interferon gamma up-regulates in vivo and down-regulates in vitro monocyte CD14 antigen expression in cancer patients.
The expression of the monocyte membrane glycoprotein CD14 was measured and related to the serum interferon gamma (IFN gamma) concentration in thirteen patients with disseminated cancer during treatment with human recombinant interferon gamma (rIFN gamma). The drug was administered by continuous subcutaneous infusion using an escalating dose schedule, starting at 50 micrograms/day or 100 micrograms/day and increasing weekly up to 600 micrograms/day, if tolerated. Treatment was continued at a mean maximal tolerated dose of 200 micrograms/day for a median duration of 43 days. Serum IFN gamma concentration and monocyte CD14 antigen expression (immunofluorescence with the monoclonal antibody LeuM3 and fluorescence-activated cell sorting analysis) were determined weekly. The serum IFN gamma concentration was positively correlated with the rIFN gamma dose (P less than 0.05). Therapy induced a dose-dependent enhancement of CD14 antigen expression. The increase in mean CD14 fluorescence intensity was on average 60% after 3 weeks of treatment at a mean dose of 220 micrograms rIFN gamma/day and was reversed after withdrawal of therapy. Patients with a rapidly rising serum IFN gamma concentration (starting dose 100 micrograms/day) showed a smaller increment in CD14 fluorescence intensity than those with slowly rising serum IFN gamma levels (starting dose 50 micrograms/day). Since rIFN gamma is known to down-regulate CD14 antigen expression in vitro, monocytes from patients off therapy and from healthy volunteers were cultured with this cytokine. A similar decrease of CD14 fluorescence was observed in both groups. In patients several factors, such as IFN gamma concentration, duration of drug effect and type of serum, were evaluated and could not explain the discrepant in vivo and in vitro findings. In conclusion, the monocyte marker CD14 was found to be differentially regulated by rIFN gamma in vivo and in vitro. In vivo, secondary mediators, induced by rIFN gamma and acting on a constantly renewed cell population, may contribute to the enhanced CD14 expression.
Department of Research and Internal Medicine, University Hospital, Basel, Switzerland.
R
R
Landmann
M
M
Wesp
C
C
Ludwig
R
R
Obrist
C
C
Knüsli
J P
JP
Obrecht
D000328:Adult; D000368:Aged; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D018950:Lipopolysaccharide Receptors; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology; D011994:Recombinant Proteins; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
D015214:Antigens, Differentiation, Myelomonocytic; D000951:Antigens, Neoplasm; D018950:Lipopolysaccharide Receptors; D011994:Recombinant Proteins; D007371:Interferon-gamma