SHP-1 As a Critical Regulator of Mycoplasma pneumoniae-Induced Inflammation in Human Asthmatic Airway Epithelial Cells

Abstract

Asthma is a chronic inflammatory disease in which airway epithelial cells are the first line of defense against exposure of the airway to infectious agents. Src homology protein (SHP)-1, a protein tyrosine phosphatase, is a negative regulator of signaling pathways that are critical to the development of asthma and host defense. We hypothesize that SHP-1 function is defective in asthma, contributing to the increased inflammatory response induced by Mycoplasma pneumoniae, a pathogen known to exacerbate asthma. M. pneumoniae significantly activated SHP-1 in airway epithelial cells collected from nonasthmatic subjects by bronchoscopy with airway brushing but not in cells from asthmatic subjects. In asthmatic airway epithelial cells, M. pneumoniae induced significant PI3K/Akt phosphorylation, NF-κB activation, and IL-8 production compared with nonasthmatic cells, which were reversed by SHP-1 overexpression. Conversely, SHP-1 knockdown significantly increased IL-8 production and PI3K/Akt and NF-κB activation in the setting of M. pneumoniae infection in nonasthmatic cells, but it did not exacerbate these three parameters already activated in asthmatic cells. Thus, SHP-1 plays a critical role in abrogating M. pneumoniae-induced IL-8 production in nonasthmatic airway epithelial cells through inhibition of PI3K/Akt and NF-κB activity, but it is defective in asthma, resulting in an enhanced inflammatory response to infection.

Capsular Polysaccharide is a Main Component ofMycoplasma ovipneumoniaein the Pathogen-Induced Toll-Like Receptor-Mediated Inflammatory Responses in Sheep Airway Epithelial Cells

“…Additionally, it plays a key role in regulating adaptive immune responses via expressing pattern recognition receptors such as toll-like receptors (TLRs) to trigger host defense responses, by interacting with dendritic cells to regulate antigen sensitization and by releasing cytokines and chemokines to recruit effector cells [19, 21]. Therefore, airway epithelial cells serve as a bridge between innate and adaptive immunity via acting as initiators, mediators, and regulators.…”

“…Airway epithelium has recently been recognized as the first line of defense against M. pneumoniae infection, which is responsible for initiating an innate immune response by producing various array inflammatory mediators thus mediating lung inflammation [ 15 , 19 , 20 ]. Additionally, it plays a key role in regulating adaptive immune responses via expressing pattern recognition receptors such as toll-like receptors (TLRs) to trigger host defense responses, by interacting with dendritic cells to regulate antigen sensitization and by releasing cytokines and chemokines to recruit effector cells [ 19 , 21 ]. Therefore, airway epithelial cells serve as a bridge between innate and adaptive immunity via acting as initiators, mediators, and regulators.…”

Macrophage-Activating Lipopeptide-2 Requires Mal and PI3K for Efficient Induction of Heme Oxygenase-1

“…As a result, inflammatory cells are activated and secrete a spectrum of cytokines and chemokines [5], [6]. These cytokines consist of a complicated synergetic or antistatic network and have been implicated in many disordered inflammatory diseases [7], [8].…”

A phosphoproteomic study reveals shp-1 cleavage reprograms LPS signaling via a PI-3K/NF-κB and mTORC1 related mechanism

“…Since shp-1 has been further reported to negatively modulate various types of inflammatory responses, both in vitro and in vivo [20][21][22][23], cleavage/degradation of shp-1 triggered by sequential H 2 O 2 and LPS stimulation will probably release its negative control on the LPS pathway and consequently lead to augmented inflammatory responses. Hence, we selected shp-1 as the primary target for the downstream functional study.…”