PARP-14, a member of the B aggressive lymphoma family, transduces survival signals in primary B cells.

Poly(ADP-ribos)ylation is one of the longest-known but most enigmatic posttranslational modifications transducing specific signals. The enzyme responsible for the majority of poly(ADP-ribose) polymerization in cells, PARP-1, promotes DNA repair but also mediates a caspase-independent form of apoptosis in response to stressors such as irradiation. However, the biologic function of most other PARPs is not known. Macro-PARPs constitute one branch of the large family of PARP-like proteins also designated as B aggressive lymphoma proteins (BAL1, 2a/2b, 3, or PARP-9, PARP-14, and PARP-15). To elucidate biologic role(s) of a BAL-family macro-PARP, we analyzed mice deficient in PARP-14, a binding partner of the IL-4-induced transcription factor Stat6. We show here that PARP-14 plays a fundamental role mediating protection against apoptosis in IL-4-treated B cells, including that after DNA damage, and mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. Collectively, the results establish that PARP-14 mediates regulation of gene expression and lymphocyte physiology by IL-4 and has a function distinct from PARP-1. Furthermore, the findings suggest mechanisms by which BAL-family proteins might influence pathologic processes involving B lymphocytes.

Up-regulation of host cell genes during interferon-gamma-induced persistent Chlamydia pneumoniae infection in HL cells.

As a step toward understanding the role played by host gene expression in the development and pathogenesis of persistent Chlamydia pneumoniae infection, modulation of the host-cell transcriptional response during interferon (IFN)- gamma -induced persistent C. pneumoniae infection of HL cells was examined by a cDNA array and then selectively by a real-time quantitative reverse transcription-polymerase chain reaction. We identified 9 host cell genes whose transcription was consistently altered during IFN- gamma -induced persistent C. pneumoniae infection. The strongest up-regulation of persistent infection, compared with controls (active infection and IFN- gamma ) was identified for insulin-like growth factor-binding protein 6, IFN-stimulated protein 15 kDa, cyclin D1, and interleukin-7 receptor genes. These results suggest that, during persistent infection, C. pneumoniae reprograms the host transcriptional machinery that regulates a variety of cellular processes, including adhesion, regulation of the cell cycle, growth, and inflammatory response, all of which might play important roles in the pathogenesis of persistent C. pneumoniae infection.

Autoimmune regulator induced changes in the gene expression profile of human monocyte-dendritic cell-lineage.

The autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymic medullary epithelial cells and in the cells of the monocyte-dendritic lineage both in the thymus and in the secondary lymphoid organs. Mutations in the AIRE gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a recessively inherited disease characterized by loss of immunological self-tolerance to multiple endocrine organs. Recent mouse knockout studies suggest that AIRE is responsible for ectopic expression of peripheral self-antigens in the thymus. In the present study, we detected an increased level of endogenous AIRE expression during the differentiation process of the human monocyte derived dendritic cells (MoDCs). We subsequently identified candidates for AIRE-regulated genes by using cDNA microarray technology to analyse the changes in the gene expression profile brought about by overexpressing the AIRE protein in the monocytic U937 cells. The changes observed resembled those previously reported to occur during the maturation of DCs, including up-regulation of the CCL22, CD25, ICAM-1 and RelB genes. In contrast, increased expression of the steroidogenic enzymes P450c17, P450c21 and P450scc, the major autoantigens in APECED, was not found either in our cell model or in the dendritic cell cultures. We also identified the ERK signal transduction pathway as a candidate for mediating the signal that results in the altered expression profile. Our findings suggest that the role of AIRE in the DCs differs from its function in the thymus.