Constitutive Activation of Phosphatidylinositol 3-Kinase Signaling Pathway Down-regulates TLR4-mediated Tumor Necrosis Factor-α Release in Alveolar Macrophages from Asymptomatic HIV-positive Persons in Vitro

MyD88-dependent TLR4 signaling is selectively impaired in alveolar macrophages from asymptomatic HIV+ persons

“…The observed differences in TLR4-mediated TNF␣ and IL-10 release were not related to differences in macrophage expression of essential TLR4 modulator molecule MD2 30 ( Figure 2G) or surface expression of TLR4 coreceptor CD14 ( Figure 2H), consistent with our prior studies showing similar TLR4 surface expression comparing U937 and HIV ϩ U1 macrophages 7,31 and comparing AMs from healthy and HIV ϩ persons. 8 In contrast to impaired TLR4-mediated MyD88-dependent release of TNF␣, collectively these data show that TLR4-mediated IL-10 and RANTES release in human macrophages is predominantly MyD88 independent and suggest that HIV may specifically target the MyD88-dependent TLR4 signaling pathway, while preserving the MyD88-independent TLR4 signaling pathway.…”

“…7 Increased susceptibility may be in part related to reduced alveolar macrophage extracellular signalregulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase phosphorylation attributed to elevated MAP kinase phosphatase 1 (MKP-1) activity, 7 and constitutive phosphoinositol-3 kinase (PI3K) activation and heightened PI3K signaling in response to TLR4 activation. 8 These data suggest that the host cell proinflammatory cytokine may be suboptimal in the lungs of HIV ϩ persons and may in part contribute to increased bacterial pneumonia susceptibility and pathogenesis.TLR4 is the most studied of the TLR family of innate receptors. 9 It is a unique member of the TLR family of mammalian receptors in that TLR4 is capable of both adaptor molecule myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent signaling.…”

“…17 Recent work in our laboratory has shown impaired TLR4-mediated signaling response in alveolar macrophages from asymptomatic HIV ϩ persons at high clinical risk of bacterial pneumonia. 7,8 However, whether both MyD88-dependent and MyD88-independent pathways are impaired by HIV infection is not known. With the use of human macrophage cell lines and clinically relevant human alveolar macrophages, the purpose of this study was to further examine the influence of HIV infection on TLR4-mediated intracellular signaling in greater detail, focusing on MyD88-dependent and MyD88-independent TLR4 signaling pathways.…”

An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpes viridae

“…After written informed consent was obtained, peripheral blood (PB) samples were obtained from patients enrolled in the Phase I dose-escalation study, as an ancillary study to better characterize the toxicity observed in the clinical study. 13 Patients bearing advanced/metastatic solid tumors were treated with repeated cycles of PHA-793887 administered as a 1 hour IV infusion on day 1, 8, 15 of a 4-week cycle, i.e., with treatment on days 1, 8, 15 followed by a 2 week resting period (day [16][17][18][19][20][21][22][23][24][25][26][27][28]. In 3 patients, before and after each injection, heparinized blood was taken on days 0, 2, 14 and 16 ( Fig.…”

“…Tumor associated-mutations deregulate distinct CDKcyclin complexes causing unscheduled proliferation. Deregulation of CDK4 and CDK6 activities have been implicated in a variety of human malignancies, CDK4 being hyperactive in epithelial a 4-week cycle, i.e., with treatment on days 1, 8, 15 followed by a 2-week resting period (day [16][17][18][19][20][21][22][23][24][25][26][27][28] (Fig. 1A).…”