Costimulation of resting B lymphocytes alters the IL-4-activated IRS2 signaling pathway in a STAT6 independent manner: implications for cell survival and proliferation

Abstract

IL-4 is an important B cell survival and growth factor. IL-4 induced the tyrosine phosphorylation of IRS2 in resting B lymphocytes and in LPS-or CD40L-activated blasts. Phosphorylated IRS2 coprecipitated with the p85 subunit of PI 3' kinase in both resting and activated cells. By contrast, association of phosphorylated IRS2 with GRB2 was not detected in resting B cells after IL-4 treatment although both proteins were expressed. However, IL-4 induced association of IRS2 with GRB2 in B cell blasts. The pattern of IL-4-induced recruitment of p85 and GRB2 to IRS2 observed in B cells derived from STAT6 null mice was identical to that observed for normal mice. While IL-4 alone does not induce activation of MEK, a MEK1 inhibitor suppressed the IL-4-induced proliferative response of LPS-activated B cell blasts. These results demonstrate that costimulation of splenic B cells alters IL-4-induced signal transduction independent of STAT6 leading to proliferation. Furthermore, proliferation induced by IL-4 in LPS-activated blasts is dependent upon the MAP kinase pathway.

IL-4 protects the B-cell lymphoma cell line CH31 from anti-IgM-induced growth arrest and apoptosis: contribution of the PI-3 kinase/AKT pathway

“…These effects are thought to be regulated by the STAT6-mediated induction of Bcl-xL [14,50,55]. In contrast, IL-4 was able to substantially protect B cells isolated from STAT6-deficient animals from spontaneous apoptosis [13,15], indicating the contribution of another signaling pathway. Therefore, a detailed understanding of the mechanism(s) by which IL-4 and IL-13 regulate cell cycle and suppress apoptosis could provide important targets for cancer therapy.…”

“…In both cases, the responses were shown to be mediated by the induction of Bcl-xL via the activation of STAT6. However, this is not the case for resting B cells; IL-4 did not induce the expression of Bcl-xL (or Bcl-2) in resting B cells [3] and was able to protect B cells isolated from STAT6-deficient animals from spontaneous apoptosis [13,15]. Thus, there is no general consensus on the mechanism by which IL-4 regulates cell survival in primary or transformed cells.…”

The Anti-Inflammatory Effects of Taif Punica Granatum in Cytokines Production in PBMCS of Patients With Rheumatoid Arthritis (Ra).

“…P. granatum acetone and ethyl acetate extracts did not showed any significant difference in IFN-γ production ( (Figure 1 C&D). In this study, P. granatum methanol and aqueous extracts in ranges (10-200 μg/ml) increased IL-4 production significantly (Figure 2 A& B), this could be related to the expansion of B cells as IL-4 is an important B cell survival and growth factor [22]. IL-4 stimulates the development of type 2 helper T cells (Th2) and inflammation nevertheless could be inhibited by TGF-β and IL-10 cytokines [23].…”

Sequential Serum Cytokine Levels of TNF-Alpha, IL-4 and IL-12 are Associated with Prognosis in Plasmodium falciparum Malaria

“…IL-4 plays an essential role by promoting Th2 cell differentiation while inhibiting Th1 cell ?differentiation [22]. IL-4 is also able to protect lymphoid cells from apoptosis [23,24], but it is unable to promote proliferation of small resting lymphocytes without a co-stimulatory signal such as that provided through antigen receptor engagement [27]. The effects of IL-4 are not restricted to lymphoid cells.…”