Our group has revealed important roles of vitamin A and cAMP in regulating proliferation and death of cells in the immune system.

In line with its well established function as a stimulator of the immune system, we could demonstrate that retinoic acid (RA) potently acts as a co-activator of human T-cells via induction of IL-2 (Ertesvåg et al (2002) J Immunol 169,5555; Engedal et al (2006) J Immunol 177,2851).

More surprising was our early finding of RA as a potent inhibitor of B-cell proliferation (Blomhoff et al (1992) J Biol Chem 267,23988; Naderi et al (1999) Blood 94,1348).

Later we could explain this unexpected role of RA, by demonstrating that whereas RA inhibits naïve B cells, it potently stimulates memory B-cells activated via toll like receptor 9 (TLR9) (Ertesvåg et al (2007) Blood 109,3865) and RP105 (Eriksen et al. (2012) Cell Immunol 279, 87.   We have recently demonstrated that TLR9/RP105-mdiated responses, and in particular IgG synthesis, is greatly diminished in B cells from patients with Common variable immune deficiency (CVID). Importantly we discovered that RA is able to restore or improve these defects (Indrevær et al. (2013) J Immunol,191, 3624; Indrevær et al, (2015) J Immunol, 195, 2601), and how it affects autophagy in the cells (Eriksen et sl, (2015), Autophagy, 11, 460). We have also revealed how RA affects DNA damage responses in normal and malignant B cells as well as in CVID-derived B cells (Holm et al, (2016), Immunology 149, 62; Holm et al, (2018) Plos One 12, e0185708). These findings may have important implications for therapy of these patients.  More recently, we have established an important role of ROS in production of IgG versus IgM in B cells (Gilljam et sl. (2020) J Immunology 204, 2133), and we are currently exploring the interplay between ROS and autophagy in normal versus CVID-derived B cells. 

We early demonstrated that the second messenger cAMP acts as an inhibitor of B cell proliferation (Christoffersen et al (1994) Cancer Res 54,2245) via its key target cyclin D3 (Gützkow et al (2002) J Cell Science 115,1073; Låhne et al (2006) Oncogene 25,2468).  

We  have also revealed that cAMP inhibits DNA damage induced-apoptosis in BCP-ALL cells (Naderi et al (2005) Mol Biol Cell 16,1527) via destabilization of p53 (Naderi et al (2009) Blood 114,608; Naderi etal., (2011) Neoplasia 13, 653; Kloster et al. (2013) Int J Oncol, 42, 1815). Importantly, we have also shown that  normal counterparts of the ALL cells in the bone marrow are unaffected by cAMP (Naderi et al, (2013 Blood) 121, 1805, a finding that has important implications for the role of cAMP in development and treatment of BCP-ALL. We showed that the ALL cells in the bone marrow were exposed to prostaglandine 2 (PGE2) from bone marrow-derived stromal cells (Naderi et al. (2015), Mol Cancer, 14, 14). Recently, we established a xenograft model of ALL in NSG mice to show that reduced production of PGE2 by Indomethacin delayed the progression of ALL (Richartz et al., (2019) Blood Advances 3, 3181).  We have also shown that enhanced autophagy is involved in cAMP-mediated protection against irradiation-induced cell death (Skah et al (2018) Oncotarget 9, 30343), and we recently established a link between ROS and the DNA repair enzyme PARP1 in this process (Richartz et al, (2021) Mol Cancer Res, Des 8: doi: 10, 1158/1541-7786 ahead of print).  We are currently linking these events to deregulated metabolism in ALL cells. 

Published Mar. 7, 2011 11:04 AM - Last modified Jan. 6, 2022 1:55 PM