Dysregulation of p38 and MKP-1 in Response to NOD1/TLR4 Stimulation in Sarcoid Bronchoalveolar Cells

Abstract

Rationale: Sarcoidosis is a systemic inflammatory disorder characterized by distinct up-regulation of Th1 cytokines, such as tumor necrosis factor (TNF)-a and IL-12. The mechanism underlying this up-regulation remains unclear. Recognition of microbial moieties through Toll-like or Nod-like receptors evokes sequential activation of mitogen-activated protein kinases (MAPKs), which plays a role in Th1-immune response. Objectives: To test the hypothesis that dysregulation in MAPK signaling in response to microbial stimulation is important in mediating Th1 response in sarcoidosis. Methods: Ex vivo cultured bronchoalveolar lavage (BAL) cells isolated from patients with sarcoidosis and control subjects were stimulated with low-dose Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 1 (NOD1) ligands as a model of microbial stimulation, and MAPK signaling and inflammatory response were analyzed. Measurements and Main Results: BAL cells from patients with sarcoidosis exhibited higher basal p38 activity, greater p38 phosphorylation, and more robust production of TNF-a and IL-12/IL-23p40 on stimulation with NOD1 and TLR4 agonists than cells isolated from control subjects. In contrast, control BAL cells had greater basal extracellular signal-regulated kinase (ERK) activity and NOD1 and TLR4 agonists preferentially activated the ERK pathway. Inhibition of p38, but not ERK, attenuated production of both IL12/IL23p40 and TNF-a. Interestingly, stimulation of cells from patients with sarcoidosis with either NOD1 or TLR4 ligand failed to induce MAPK phosphatase 1 (MKP-1). Adenovirus-mediated overexpression of MKP-1 attenuated p38 activation and decreased the production of IL12/IL23p40 and TNF-a in sarcoid BAL cells. Conclusions: Our results suggest that enhanced p38 signaling in response to microbial products is caused by abnormal regulation of MKP-1 and contributes to heightened inflammation in sarcoidosis.

Etiologies of Sarcoidosis

“…Stimulation of the nucleotidebinding oligomerization domain 1 (NOD1) results in enhanced expression of TNF and IL12/IL23 p40 in a subset of sarcoidosis patients [43]. Of interest, mutations in the NOD2 gene are strongly associated with a clinical triad of joint, eye, and skin involvement observed in a subset of pediatric sarcoidosis cases [44], although this linkage does not appear to Genetic-environmental interactions • Heightened risk for extra-pulmonary disease associated with exposures (insecticide, molds, and musty odors) in HLA-DRB1*1101 patients be present in adult sarcoidosis [45][46][47][48].…”

Pathogenesis of sarcoidosis

“…Conflicting results have been obtained for TLR4 gene variants in Caucasian and Japanese cohorts [107,108], which point to a causative variation in the vicinity of the TLR4 gene [109]. Nevertheless, an increased expression of TLR2, TLR4, and TLR9 and their signal transduction is observed in sarcoidosis [110][111][112]. TLRs are members of the pattern recognition receptors involved in microbial defence.…”

Update in Diffuse Parenchymal Lung Disease 2011

“…Thus, in susceptible individuals, inanimate remnants of bacteria or remote infection may be capable of inducing sustained sarcoid-like inflammation (51,52). The nature of these disease susceptibilities may be queried in genome-wide association studies, which have identified a number of gene variants associated with sarcoidosis and other granulomatous disorders (53)(54)(55).…”