This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

The relaxin-like RXFP1 ligand–receptor system has important functions in tumor growth and tissue invasion. Recently, we have identified the secreted protein, CTRP8, a member of the C1q/tumor necrosis factor-related protein (CTRP) family, as a novel ligand of the relaxin receptor, RXFP1, with functions in brain cancer. Here, we review the role of CTRP members in cancers cells with particular emphasis on CTRP8 in glioblastoma.

The C1q/TNF‐related peptide 8 (CTRP8) has recently emerged as a novel ligand of the G protein‐coupled receptor RXFP1 in the fatal brain tumor glioblastoma (GBM). We previously demonstrated that the CTRP8‐RXFP1 ligand–receptor system promotes motility and matrix invasion of patient GBM and U87 MG cells by specific phosphorylation of PI3 kinase and protein kinase C. Here, we demonstrate a novel role for CTRP8 in protecting human GBM cells against the DNA alkylating damage of temozolomide (TMZ), the standard chemotherapy drug used to treat GBM. This DNA protective role of CTRP8 required a functional RXFP1‐STAT3 signaling cascade in GBM cells. We identified N‐methylpurine DNA glycosylase (MPG), a monofunctional glycosylase that initiates base excision repair pathway by generating an apurinic/apyrimidinic (AP) site, as a new CTRP8‐RXFP1‐STAT3 target in GBM. Upon TMZ exposure, treatment with CTRP8 reduced the formation of AP sites and double‐strand DNA breaks in GBM cells. This CTRP8 effect was independent of cellular MGMT levels and was associated with decreased caspase 3/7 activity and increased survival of human GBM. CTRP8‐induced RXFP1 activation caused an increase in cellular protein levels of the anti‐apoptotic Bcl members and STAT3 targets Bcl‐2 and Bcl‐XL in human GBM. Collectively, our results demonstrate a novel multipronged and clinically relevant mechanism by which the CTRP8‐RXFP1 ligand–receptor system exerts a DNA protective function against TMZ chemotherapeutic stress in GBM. This CTRP8‐RXFP1‐STAT3 axis is a novel determinant of TMZ responsiveness/chemoresistance and an emerging new drug target for improved treatment of human GBM.

Objective Tumour necrosis factor α (TNFα) blockade in spondyloarthritis (SpA) induces antibodies specifi c for double stranded DNA, which is a T cell independent (TI) antigen. As these antibodies were restricted to the IgM isotype and no antibodies to T cell dependent (TD) antigens were induced, we investigated here if TNF blockade impairs the induction and maturation of TD humoural responses. Methods 30 SpA patients (20 treated with TNFα blockade, 10 untreated controls) were vaccinated with a TD vaccine to hepatitis B and a TI vaccine to S pneumoniae. Another 10 SpA patients treated with infl iximab were vaccinated with a TD vaccine to S pneumoniae. Serum and peripheral blood mononuclear cells were collected before and after vaccination. Vaccine-specifi c antibody titres were measured by ELISA. B and T cell populations were evaluated by fl ow cytometry. Somatic hypermutation was determined by the Igκ REHMA assay (Andersen, Blood 2005). Results IgM and IgG responses against TI antigens were moderately decreased in anti-TNFα treated patients compared to controls but were still robust. In contrast, IgG responses against TD antigens were almost completely absent in treated patients. The greater suppression of TD versus TI responses by TNFα blockade was confi rmed by lower IgG titres with TD versus TI vaccines against anti-S pneumoniae. Phenotypic analysis showed a normal number of B cells but a decrease in naïve and memory CD4 T cells upon TNFα blockade. Within the B cell population, TNF blockade signifi cantly increased the frequency of memory B, which displayed an activated phenotype with increased expression of CD40 and HLA-DR. In parallel, however, TNF blockade decreased the frequency of CD138 plasmablasts, suggesting a defective maturation towards antibody-producing cells. Moreover, TNF blockade signifi cantly decreased the degree of somatic hypermutation as evidenced by Igκ REHMA analysis of peripheral blood B cells before and after treatment. Conclusion TNF blockade severely impairs TD humoural responses by interfering with the affi nity maturation and differentiation of activated B cells towards antibody producing cells.