Fas-stimulated neutrophils from elderly individuals show impaired granulocyte macrophage-colony-stimulating factor (GM-CSF)-induced apoptosis cell rescue. Herein, this defect was found to be associated with a significant reduction in GM-CSF-mediated Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Using Akt and ERK1/2 inhibitors, we demonstrated that both kinases were critical for GM-CSF antiapoptotic effects. Whereas Akt inhibition also affected GM-CSF-dependent ERK1/2 phosphorylation, ERK1/2 inhibition did not affect GM-CSF-induced Akt phosphorylation, suggesting that phosphoinositide 3-kinase (PI3-K)/Akt and ERK1/2 are activated in series and that PI3-K is located upstream of ERK1/2 along the GM-CSF-dependent signaling pathway. No age-associated changes in GM-CSF receptor expression were observed. Interestingly, both suppressors of cytokine signaling (SOCS)1 and SOCS3 proteins were significantly higher in unstimulated neutrophils from elderly individuals and, unlike in young individuals, did not further increase following GM-CSF cell triggering. These results indicate that defective PI3-K/Akt/ERK1/2 activation, likely dependent on elevated SOCS1 and SOCS3 levels, may affect the GM-CSF capacity to delay neutrophil apoptosis in elderly persons.
Chronic malaria severely affects the immune system and causes polyclonal B-cell activation, as evidenced by the presence of hypergammaglobulinemia, elevated levels of autoantibodies, loss of B-cell memory and the frequent occurrence of Burkitt’s lymphomas (BL) in children living in malaria endemic areas.
Previous studies have shown that the cysteine-rich interdomain region 1α (CIDR1α) of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) of the FCR3S1.2 strain, subsequently named CIDR1α, interacts with B cells partially through the binding to the B-cell receptor (BCR). This interaction leads to an activated phenotype, increased survival, and a low degree of proliferation. CIDR1α preferentially activates the memory B-cell compartment, therefore PfEMP1 is considered to act as a polyclonal B-cell activator and its role in memory maintenance has been suggested.
In this report, we extend the analysis of the PfEMP1–CIDR1α B-cell interaction and demonstrate that PfEMP1–CIDR1α increases the expression of TLR7 and TLR10 mRNA transcripts and sensitizes B cells to TLR9 signalling via the MyD88 adaptor molecule. Furthermore, despite its ability to bind to surface Igs, PfEMP1–CIDR1α-induced B-cell activation does not seem to proceed through the BCR, since it does not induce Lyn and/or phospho-tyrosine mediated signalling pathways. Rather PfEMP1–CIDR1α induces the phosphorylation of downstream kinases, such as ERK1/2, p38 and IKBα, in human B cells. These findings indicate that PfEMP1–CIDR1α induces a persistent activation of B cells, which in turn can contribute to the exhaustion and impairment of B-cell functions during chronic malaria infection.
Our data suggest that a TLR7-dependent impairment of costimulatory molecule expression caused by HCV persistence may affect DC activity in NR patients.
Interleukin (IL)-12 is the major inducer of T helper cell (Th) 1-type responses. Despite a higher IL-12 production, phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC), as well as CD4(+) or CD8(+) T cells from elderly donors released interferon (IFN)-gamma amounts similar to those observed in young controls, and underwent only a slight increase in IFN-gamma production after IL-12 costimulation. These findings were not due to an age-related reduction in IL-12 receptor expression. Interestingly, no difference in PHA-triggered signal transducer and activator of transcription 4 (STAT4) phosphorylation between young and elderly donors was found, and a significant IL-12-induced STAT4 activation occurred only in PHA-preactivated cells from the younger group. The age-related defect in IL-12 signaling was STAT4-restricted as it did not involve the p38 mitogen-activated protein kinase (MAPK) pathway. Finally, suppressor of cytokine signaling 3 (SOCS3) expression was significantly higher in unstimulated cells from elderly individuals, and it did not diminish after cell stimulation. These results indicate that a defective STAT4 activation, likely dependent on elevated SOCS3 levels, is involved in the impaired IL-12-dependent T-cell functions with aging.
Endometriosis is an estrogen-correlated benign disease characterized by a marked ability of endometrial-like cells to invade and proliferate outside uterine cavity, resembling for some invasive aspect the cancer growth. The molecular mechanisms regulating endometrial cell invasiveness are mostly unknown, although interactions between extracellular matrix (ECM) proteins and their transmembrane receptors, integrins, are likely to play a central role. In particular, laminin (Ln)-5 could be closely involved, as it is in cancer. We have investigated the expression of Ln-1, Ln-5, and collagen IV (Coll IV) ECM proteins and their receptors, alpha3beta1 and alpha6beta4 integrins, in atrophic, proliferative, and secretive endometrium and in endometriosis. The results show that Ln-5, but not Ln-I and Coll IV, is altered in secretive endometrium as well as in endometriosis tissues. No alterations are observed in atrophic or proliferative endometrium. Consistently, the polarization of both integrin subunits alpha3 and beta1, but not alpha6 and beta4, is altered in secretive endometrium and endometriosis tissues, but not in atrophic and proliferative endometrium. These results seem to suggest that Ln-5 and alpha3beta1 could be involved in the invasive mechanism of endometriosis. The altered expression of Ln-5, by upregulating matrix metalloproteases activity, suggest an invading process similar to that of many cancer processes.
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