Title

Inhibitors of poly(ADP-ribose) polymerase increase antibody class switching

UMMS Affiliation

Department of Molecular Genetics and Microbiology

Date

12-15-1993

Document Type

Article

Subjects

Animals; B-Lymphocytes; Cell Line; Chromosome Mapping; Cyclic AMP; Gene Rearrangement, B-Lymphocyte; Immunoglobulin A; Immunoglobulin Switch Region; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Niacinamide; Poly(ADP-ribose) Polymerases; Transforming Growth Factor beta; Xanthines

Disciplines

Life Sciences | Medicine and Health Sciences | Women's Studies

Abstract

Previous studies suggest that heavy chain isotype switch (S) recombination is directed by cytokine-induced transcription of the unrearranged CH gene before recombination. In studies aimed at identifying other signaling pathways that promote switching, we discovered that inhibitors of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) increase LPS-induced switching to IgA in the B cell lymphoma 1.29 mu and to IgG1 in LPS + IL-4-treated splenic B cells. PARP, which binds to and is activated by DNA strand breaks, catalyzes the removal of ADP-ribose from NAD+ and poly(ADP-ribosylation) of chromatin-associated acceptor proteins. This enzyme is believed to function in cellular processes involving DNA strand breaks as well as in modulating chromatin structure. In 1.29 mu cells, PARP inhibitors increase IgA switching by day 2 and cause a fivefold increase in switching on day 3 as assayed by immunofluorescence microscopy. In spleen B cells, the PARP inhibitor nicotinamide increases IgG1 switching by about twofold. Nicotinamide also causes a reduced intensity of hybridization of C mu- and C alpha-specific probes to genomic DNA fragments containing the expressed VDJ-C mu and the unrearranged S alpha-C alpha segments, respectively, in 1.29 mu cells, indicating that PARP inhibition increases rearrangement of these fragments. Induction of switching by PARP inhibitors is not mimicked by treatment with cAMP analogues or reduced by inhibitors of protein kinase A. Induction of switching by PARP inhibitors does not appear to involve increased levels of transcription of the unrearranged C alpha gene.

Rights and Permissions

Citation: J Immunol. 1993 Dec 15;151(12):6962-76.

Related Resources

Link to article in PubMed

PubMed ID

8258703