The interleukin-12 and interleukin-12 receptor system in normal and transformed human B lymphocytes

Abstract

BACKGROUND AND OBJECTIVES: Interleukin-12 (IL-12) is a heterodimeric cytokine that induces interferon-g (IFN-g) production by natural killer and T-lymphocytes. IL-12 also activates human B-cells through the IL-12 receptor (IL-12R) complex. Here we review the expression and function of IL-12 and IL-12R in human B-cells and in their malignant counterparts. EVIDENCE AND INFORMATION SOURCES: The information provided derives from results both published and unpublished obtained in the laboratories of the Authors, and from a comprehensive review of all the pertinent articles published so far in Medline. STATE OF ART: The two components of the IL-12R, i.e. the b 1 and b 2 chains, were found to be constitutively expressed in human naive, germinal center and memory tonsil B-cells; however, only naive B-cells were activated following interaction with IL-2. Here we show that the IL-12Rb2 gene is not expressed in EBV-transformed normal B-lymphocytes and in Burkitt's lymphoma B-cell lines. IL-12 p35 and p40 transcripts were detected in all tonsil B-cell subsets, but only naive and memory B-cells produced IL-12. In this study, biosynthesis of IL-12 was investigated in tonsil B-cells, showing that the molecular weight of the mature heterodimeric IL-12 was similar to that of monocyte-derived IL-12, with minor differences possibly related to glycosylation. Finally, malignant B-cells from follicular and marginal zone lymphomas expressed IL-12 p35 and p40 transcripts, whereas only p35 mRNA was detected in mantle cell lymphoma. PERSPECTIVES: Taken together, the studies herein reviewed indicate that human B-cells, at variance with their murine counterparts, can produce IL-12 following CD40 ligation. IL-12 p35 and p40 transcripts are found in B-cells from different lymphoproliferative disorders, but the evidence that the cytokine is produced at the protein level is poor. IL-12R is expressed in the main human B-cell subsets, but it is functional only in naive B-cells. Finally, the failure of transformed B-cell lines to express IL-12Rb2 mRNA opens up new perspectives in the investigation of B-cell malignant transformation.