Abstract
Heat shock proteins (HSPs) have been shown to modulate NF-κB activation. It is unknown whether HSP70 plays a role in modulating NF-κB-mediated pro-inflammatory cytokines released from alveolar macrophage (AM) of patients with active pulmonary tuberculosis (TB). Peripheral blood monocytes (PBMs) and AM were sampled from nineteen active TB patients and 14 healthy individuals. HSP70 expression was 3-fold higher in AMs of active TB patients than normal subjects, and declined after receiving 3-month anti-TB treatment. Overexpression of HSP70 by transfection with HSP70 plasmid decreased p-IκBα and p65 NF-κB activities. Inhibition of NF-κB activation using NF-κB or MAPK inhibitors increased HSP70 expression in AM of TB patients. Blocking p38- or ERK-MAPK decreased NF-κB and IκB activities, leading to up-regulated HSP70 expression. Overexpression of HSP70 alone or with p38 or ERK inhibitors decreased TNF-α (57%, 83% and 74%, respectively) and IL-6 (53%, 70%, and 67%, respectively) release from macrophages of TB patients. In conclusion, HSP70 modulates NF-κB activation in AM of TB patients, through inhibiting IκB-α phosphorylation or acting as a chaperon molecule to prevent NF-κB binding to the target genes by facilitating degradation. The upregulated HSP70 may suppress the release of pro-inflammatory cytokines during active PTB infection, and prevent overwhelming tissue damage.
Highlights
Tuberculosis (TB) remains a major health problem worldwide[1]
Our present study has demonstrated that HSP70 expression is upregulated in alveolar macrophages (AM) of patients with active TB and inhibits NF-κB-mediated tumor necrosis factor (TNF)-α and IL-6 release
The upregulated expression of HSP70 in AM decreased after effective anti-TB treatment, and was not seen in the peripheral blood monocytes, suggesting HSP70 upregulation is attributed to a direct exposure of AM to Mycobacterium TB
Summary
Tuberculosis (TB) remains a major health problem worldwide[1]. Clinical and pathologic features of TB depend at least in part on the orchestrated secretion of a number of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. Our previous report demonstrated that alveolar macrophages (AM)[4] or monocytes[5] from patients with active pulmonary TB may release pro-inflammatory cytokines TNF-α and IL-1β via NF-κB activation. Pathogen recognition by toll-like receptors (TLRs) and downstream TLR signaling play an important role in activation of innate immune cells and prevent excessive T cell-mediated inflammation[12]. Upon stimulation with TLR4 ligand such as LPS downstream TLR/MyD88-dependent signaling results in activation of NF-κB-mediated transcription of pro-inflammatory cytokines such as TNF-α and IL-613. Members of the HSP family may cross-talk with toll-like receptors to activate pro-inflammatory signals[14], and play an important role in granuloma formation and immune protection during M. tuberculosis infection. HSP70 may block the activation of NF-κB2, 15, 16, and inhibit cytokine-mediated NF-κB nuclear translocation and subsequent pro-inflammatory cytokine release[17]. HSP70 or inhibition of NF-κB activation, or blocking the activity of mitogen-activated protein kinases (MAPKs) that are required for persistent NF-κB activation[18]
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