Decreased production of IL-2 and IFN-gamma by stimulated splenocytes from mice bearing plasma cell tumors is associated with alteration of DNA-binding factors.
We have previously demonstrated that polyclonally stimulated splenocytes as well as enriched T cells from mice bearing plasma cell tumors (PCT) show decreased production of the Th1-associated cytokines, IL-2 and IFN-gamma. This observed loss of IL-2 and IFN-gamma production could be attributed to possible alterations in various factors required for T cell activation and cytokine production. We find that B7 co-stimulatory molecules and IL-2R are up-regulated normally on splenocytes from PCT mice. Concanavalin A (Con A) stimulation of splenocytes from PCT mice in the presence of immobilized anti-CD28 antibody does not enhance proliferation. Exogenous rIL-2 addition to cultures of splenocytes from PCT mice also does not enhance proliferative responses or cytokine production. Furthermore, we do not observe inhibition of normal splenocyte proliferation and IL-2 production in the presence of splenocytes from PCT mice, suggesting that the appearance of suppressor cells cannot account for the decreased responses by splenocytes from PCT mice. Also, IL-2 mRNA levels are decreased in stimulated splenocytes from PCT mice, suggesting that there may be an alteration of transcription factors required for activation of IL-2. Therefore, we have evaluated the DNA-binding activity of transcription factors involved in activation of IL-2 and IFN-gamma gene transcription. We find that binding activities of AP-1, Oct-1 and Oct-2 transcription factors in stimulated splenocytes from PCT mice are similar to normal splenocytes. However, the binding activities of NF-kappa B complexes and factors that bind to the proximal conserved element in the IFN-gamma promoter are dramatically altered in splenocytes from PCT mice. These results suggest that PCT induce changes in certain transcription factors that are important for anti-tumor responses, including T cell proliferative responses and Th1-associated cytokine production.
Ruzek
M C
MC
Department of Microbiology, University of Minnesota, Minneapolis 55455, USA.
O'Brien
D P
DP
Mathur
A
A
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D018122:B7-1 Antigen / Q000096:biosynthesis; D018106:CD28 Antigens / Q000276:immunology; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D005260:Female; D051863:Host Cell Factor C1; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; D010954:Plasmacytoma / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism* / Q000494:pharmacology*
D000906:Antibodies; D018122:B7-1 Antigen; D018106:CD28 Antigens; D004268:DNA-Binding Proteins; C497693:Hcfc1 protein, mouse; D051863:Host Cell Factor C1; D007376:Interleukin-2; D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; C494166:Pou2f1 protein, mouse; C489206:Pou2f2 protein, mouse; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D007371:Interferon-gamma