IL-32, a Novel Proinflammatory Cytokine in Chronic Obstructive Pulmonary Disease

193

192

Monocyte exposure to LPS induces a transient state in which these cells are refractory to further endotoxin stimulation. This phenomenon, termed endotoxin tolerance (ET), is characterized by a decreased production of cytokines in response to the proinflammatory stimulus. We have established a robust model of ET and have determined the time frame and features of LPS unresponsiveness in cultured human monocytes. A large number of genes transcribed in tolerant monocytes were classified as either "tolerizable" or "nontolerizable" depending on their expression levels during the ET phase. Tolerant monocytes exhibit rapid IL-1R-associated kinase-M (IRAK-M) overexpression, high levels of triggering receptor expressed on myeloid cells-1 (TREM-1) and CD64, and a marked down-regulation of MHC molecules and NF-B2. These cells combine potent phagocytic activity with impaired capability for Ag presentation. We also show that circulating monocytes isolated from cystic fibrosis patients share all the determinants that characterize cells locked in an ET state. These findings identify a new mechanism that contributes to impaired inflammation in cystic fibrosis patients despite a high frequency of infections. Our results indicate that a tolerant phenotype interferes with timing, efficiency, and outcome of the innate immune responses against bacterial infections.

Section: Discussionmentioning

confidence: 99%

Potent Phagocytic Activity with Impaired Antigen Presentation Identifying Lipopolysaccharide-Tolerant Human Monocytes: Demonstration in Isolated Monocytes from Cystic Fibrosis Patients

Fresno¹,

García‐Río

Gómez-Piña³

et al. 2009

193

192

“…The IL-32g-mediated production of the inflammatory cytokines may play an important role in inflammatory diseases, the pathogenesis of which is associated with IL-32g. Recently acquired evidence points to a pivotal role for inflammatory cytokines such as IL-12 and IL-6 in the pathogenesis of several Th1-and Th17-mediated autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, and inflammatory bowel disease (18-21) Increased IL-32g expression has been previously associated with chronic obstructive pulmonary disease, inflammatory bowel disease, rheumatoid arthritis, and psoriasis (28)(29)(30)(31). In a previous study, the knockdown of endogenous IL-32 by small interfering RNA resulted in a remarkable reduction in Th1 cytokines (26).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, IL-32 overexpression in mouse bone marrow transplantation results in increased levels of proinflammatory cytokines, exacerbates collagen-induced arthritis, and induces more profound inflammation in sulfuric acid-induced colitis (28). Elevated IL-32 expression has also been associated with chronic obstructive pulmonary disease, inflammatory bowel disease, and psoriasis (29)(30)(31). Rheumatoid arthritis patients evidenced overexpressed IL-32 from PBMCs as compared with healthy controls (32).…”

mentioning

confidence: 99%

IL-32γ Induces the Maturation of Dendritic Cells with Th1- and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

Jung

Son

Kim

et al. 2011

IL-32, a newly described multifunctional cytokine, has been associated with a variety of inflammatory diseases, including rheumatoid arthritis, vasculitis, and Crohn’s disease. In this study, we investigated the immunomodulatory effects of IL-32γ on bone marrow-derived dendritic cell (DC)-driven Th responses and analyzed the underlying signaling events. IL-32γ–treated DCs exhibited upregulated expression of cell-surface molecules and proinflammatory cytokines associated with DC maturation and activation. In particular, IL-32γ treatment significantly increased production of IL-12 and IL-6 in DCs, which are known as Th1- and Th17-polarizing cytokines, respectively. This increased production was inhibited by the addition of specific inhibitors of the activities of phospholipase C (PLC), JNK, and NF-κB. IL-32γ treatment increased the phosphorylation of JNK and the degradation of both IκBα and IκBβ in DCs, as well as NF-κB binding activity to the κB site. The PLC inhibitor suppressed NF-κB DNA binding activity and JNK phosphorylation increased by IL-32γ treatment, thereby indicating that IL-32γ induced IL-12 and IL-6 production in DCs via a PLC/JNK/NF-κB signaling pathway. Importantly, IL-32γ–stimulated DCs significantly induced both Th1 and Th17 responses when cocultured with CD4+ T cells. The addition of a neutralizing anti–IL-12 mAb abolished the secretion of IFN-γ in a dose-dependent manner; additionally, the blockage of IL-1β and IL-6, but not of IL-21 or IL-23p19, profoundly inhibited IL-32γ–induced IL-17 production. These results demonstrated that IL-32γ could effectively induce the maturation and activation of immature DCs, leading to enhanced Th1 and Th17 responses as the result of increased IL-12 and IL-6 production in DCs.

“…IL-32 (NK transcript 4), found in activated T cells, NK cells, and monocytic cells, is a potent inducer of proinflammatory mediators in diseases such as RA, atopic dermatitis, and chronic obstructive pulmonary disease (9)(10)(11). IL-32 levels are significantly elevated in RA synovial tissues and can induce joint inflammation, cartilage damage (9), and osteoclast differentiation (12).…”

mentioning

confidence: 99%

Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

Turner-Brannen

Choi

Arsenault³

et al. 2011

Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32– and IL-17–mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL-32–induced downstream responses, indicating that IL-32–mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17–induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-κB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-α and IL-1β. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL-17 overlap, and that these proteins would affect both TNF-R1–dependent and –independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases.