11 research outputs found
Differential expression of miR-4520a is associated with gain of function mutations in Familial Mediterranean Fever (FMF)
Cobalt protoporphyrin represses osteoclastogenesis through blocking multiple signaling pathways
Cobalt protoporphyrin (CoPP) is a metallo-protoporphyrin that works as a powerful inducer of heme oxigenase-1 (HO-1) in various tissues and cells. Our recent studies have demonstrated that induction of HO-1 by several reagents inhibited differentiation and activation of osteoclasts (OCLs), which are multinucleated bone resorbing cells. However, the effects of CoPP on osteoclastogenesis remain to be elucidated. In this study, we report that CoPP inhibits receptor activator of nuclear factor κB ligand (RANKL)-induced OCL formation in a dose dependent manner. Importantly, CoPP had little cytotoxicity, but rather enhanced cell proliferation of OCLs. CoPP suppressed the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1) as well as those of OCLs markers such as Src and cathepsin K, which are transcriptionally regulated by NFATc1 in mature OCLs. Western blot analyses also showed that CoPP abolished RANKL-stimulated phosphorylation of several major signaling pathways such as IκB, Akt, ERK, JNK and p38 MAPKs in OCL precursor cells. Thus, our results show that CoPP represses osteoclastogenesis through blocking multiple signaling pathways
Enhanced IL-7 receptor signaling in SLE promotes T-helper cell proliferation through upregulation of microRNA-182 and downregulation of FOXO1
Differential effects of ICOS and CD28 co-stimulation blockade on T follicular helper cells
Role of Blimp-1 in programing Th effector cells into IL-10 producers
Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an
essential mechanism of self-limitation during infection. However, the transcriptional regulation
of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood.
We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a
STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency
led to excessive inflammation during Toxoplasma gondii infection with increased mortality.
IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced
by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by
multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also
broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth
factor (TGF) . While effectively blocking IL-10 production from Th1 cells, TGF- shifted
IL-10 regulation from a Blimp-1–dependent to a Blimp-1–independent pathway in IL-27–
induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in
Th cells relies on several transcriptional programs that integrate various signals from the environment
to fine-tune expression of this critical immunosuppressive cytokine.149481sciescopu
Durch TGFbeta-induzierte Immunanergie kennzeichnet das Pediatric Inflammatory Multisystem Syndrome
The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes
After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor-mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell-mediated immune responses and open new therapeutic possibilities