Signal-transducing adaptor protein-2 delays recovery of B lineage lymphocytes during hematopoietic stress

Abstract

Signal-transducing adaptor protein-2 (STAP-2) was discovered as a C-FMS/M-CSFR interacting protein and subsequently found to function as an adaptor of signaling or transcription factors. These include STAT5, MyD88 and IκB kinase in macrophages, mast cells, and T cells. There is additional information about roles for STAP-2 in several types of malignant diseases including chronic myeloid leukemia, however, none have been reported concerning B lineage lymphocytes. We have now exploited gene targeted and transgenic mice to address this lack of knowledge, and demonstrated that STAP-2 is not required under normal, steady-state conditions. However, recovery of B cells following transplantation was augmented in the absence of STAP-2. This appeared to be restricted to cells of B cell lineage with myeloid rebound noted as unremarkable. Furthermore, all hematological parameters were observed to be normal once recovery from transplantation was complete. Furthermore, overexpression of STAP-2, specifically in lymphoid cells, resulted in reduced numbers of late-stage B cell progenitors within the bone marrow. While numbers of mature peripheral B and T cells were unaffected, recovery from sub-lethal irradiation or transplantation was dramatically reduced. Lipopolysaccharide (LPS) normally suppresses B precursor expansion in response to interleukin 7, however, STAP-2 deficiency made these cells more resistant. Preliminary RNA-Seq analyses indicated multiple signaling pathways in B progenitors as STAP-2-dependent. These findings suggest that STAP-2 modulates formation of B lymphocytes in demand conditions. Further study of this adapter protein could reveal ways to speed recovery of humoral immunity following chemotherapy or transplantation.

Potential therapeutic applications of targeting signal-transducing adaptor protein-2 in autoimmune diseases

“…Indeed, STAP-2 expression is highly induced by several inflammatory cytokines and reagents such as IL-6 and lipopolysaccharide [5], although STAP-2 mRNA is ubiquitously expressed in a variety of tissues and cells under steady-state conditions. Several mouse models of immune/ inflammatory diseases, such as inflammatory bowel disease, hematopoietic stem cell transplantation, and graft-versus-host disease, clearly show that STAP-2 expression influences the onset and development of these diseases [35][36][37].…”

STAP-2 Adaptor Protein Regulates Multiple Steps of Immune and Inflammatory Responses

“…Importantly, Stap-2 gene targeted and/or transgenic mice grew normally and did not exhibit any detrimental phenotypes in their immune systems under steady state conditions. However, several mouse models for immune/inflammatory diseases, such as inflammatory bowel diseases, 50) hematopoietic stem cell transplantation, 51) and graft-versus-host diseases, 52) clearly indicated that STAP-2 expression influenced the onset and development of these diseases. Therefore, detailed understanding of the molecular interactions between STAP-2 and its partner signaling molecules will provide useful information for the development of new drugs to control immune, inflammatory, and allergic disorders in the future.…”

The Effects of Adoptively Transferred IL-23/IL-18-Polarized Neutrophils on Tumor and Collagen-Induced Arthritis in Mice

“…The purified mouse or human neutrophils were adjusted to 1×10 6 cells/mL and added into 48 well plates. The cells were cultured with cytokines or inhibitors according to the following concentrations: [17][18][19][20][21][22][23][24] rmIL-1β (100 ng/mL), rmIL-4 (10 ng/mL), rmIL-6 (50 ng/mL), rmIL-10 (20 ng/ mL), rmIL-13 (50 ng/mL), rmIL-21 (50 ng/mL), rmIL-33 (100 ng/mL), LPS (100 ng/mL), rmIFN-γ (100 ng/mL), rmTNF-α (100 ng/mL), rmTGF-β1 (5 ng/mL), rmGM-CSF (40 ng/mL), rmG-CSF (100 ng/mL), rmIL-2 (10 ng/ mL). rmIL-12 (5 ng/mL), IL-17A (100 ng/mL), rmIL-18 (25 ng/mL), rmIL-25 (20ng/mL), JNK inhibitor (SP600125, 10 or 20 μM), A selective ERK inhibitor (PD98059, 10 or 20 μM), NF-κB inhibitor (10 or 20 μM), and P38 inhibitor (SB203580, 10 or 20 μM).…”