ALK+ALCLs induce cutaneous, HMGB-1–dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation

Abstract

IntroductionSystemic anaplastic large-cell lymphoma (ALCL) is an aggressive peripheral T-cell lymphoma. There are 2 types of ALCL, classified as anaplastic lymphoma kinase (ALK)-positive (ALK ϩ ) or ALKnegative (ALK Ϫ ) depending on whether the receptor tyrosine kinase ALK is expressed. ALK is activated most frequently through the nonrandom t(2;5) chromosome translocation, resulting in the fusion of the nucleophosmin (NPM) gene from the 5q35 locus to the 2p23 region that encodes ALK. 1,2 ALK ϩ ALCLs are characterized by frequent extranodal colonization, particularly in the skin (reported in 20%-30% of cases), and this is associated with a negative prognosis. 1 The diagnosis of cutaneous dissemination in ALK ϩ ALCL is not always easy and, in some cases, the original histopathological classification is one of "non-malignant inflammatory disease." 3 Interestingly, an insect bite could be the trigger for cutaneous ALK ϩ lymphoma metastases. Our group reported 5 cases of systemic ALK ϩ ALCL in which skin lesions presented after an insect bite at the onset of the disease, postulating that bite-associated Ags could result in an influx of T lymphocytes, some of them bearing the t(2;5) translocation. 4 The subsequent release of cytokines leading to skin inflammation at the site of the bite could act as a "second hit" eliciting activation of T lymphocytes, which would then express the oncogenic NPM-ALK protein and undergo uncontrolled proliferation and transformation. 4 ALK ϩ ALCL patients also present with an inflammatory syndrome characterized by high fever, lymphadenopathy or neutrophilia, release of various circulating inflammatory chemokines such as IL-8, 5 and expression of skin-inflammatory biomarkers such as the alarmins heat-shock protein 90 (HSP90), HSP70, 6 S100A8, or A11. 7 Recent studies have highlighted a role for IL-8 in mediating cutaneous skin inflammation and human keratinocyte hyperplasia associated with acanthosis (thickening of the skin). 8 IL-8 secreted by hyperplasic keratinocytes increases T-lymphocyte migration into the skin across both the vascular endothelium and the subendothelial matrix. 9 The high-mobility-group box-1 (HMGB-1) alarmin, also called amphoterin, is a highly conserved component of eukaryotic nuclei. 10 Interestingly, it can also be released from necrotic and tumoral cells, where it is considered an inflammatory cytokine. T-and B-cell non-Hodgkin lymphoma cells express and release high levels of HMGB-1. 11 Its extracellular form binds to inflammatory receptors, such as the receptor for advanced glycation end products (RAGE) and TLR. 12,13 HMGB-1 has also been shown to regulate matrix metallopeptidase-9 (MMP-9) levels via NF-Brelated pathways. 14,15 In ALK ϩ ALCL, we have demonstrated that MMP-9 is required for NPM-ALK ϩ cell invasiveness. 16 Moreover, MMPs stimulate protease-activated receptors (PARs). 17 Activation of PAR-2 results in the production of various cytokines and chemokines by keratinocytes, 18 leading to epidermic inflammation via increased NF-B p65 phosphorylation an...

Combined targeting of high‐mobility group box‐1 and interleukin‐8 to control micrometastasis potential in gastric cancer

“…However, its exact mechanism has not been fully evaluated. Recent studies showed that HMGB1 regulates IL‐8 secretion through NF‐κB activation, and other studies also reported that tumor‐derived IL‐8 plays a critical role in EMT of human carcinoma . Based on these results, we hypothesized that HMGB1 may induce IL‐8 over‐production in tumor microenvironment, and thereby HMGB1 contribute to EMT promotion through IL‐8 dependent manner via the HMGB1‐RAGE axis and its downstream pathways during GC progression.…”

HMGB1 in health and disease

“…Currently, a number of studies have demonstrated that HMGB1 can selectively bind multiple receptors (e.g., RAGE and TLRs) to active macrophages (He et al, 2012b), monocytes (Andersson et al, 2000), neutrophils (Park et al, 2003; Silva et al, 2007), eosinophils, astrocytes (Pedrazzi et al, 2007), fibroblasts (Guo et al, 2011; Hou et al, 2011b; Hreggvidsdottir et al, 2009), keratinocytes (Dejean et al, 2012), dendritic cells (Yang et al, 2007), natural killer cells, T and endothelial cells (e.g., vascular endothelial cells (Fiuza et al, 2003; Treutiger et al, 2003), airway epithelial cells (Kim et al, 2012a; Wolfson et al, 2011; Wu et al, 2013c), and intestinal epithelial cells (Huang et al, 2012c; Sappington et al, 2002)) to produce cytokines (e.g., TNF (Agnello et al, 2002; Andersson et al, 2000; Kim et al, 2010b; Park et al, 2003; Wu et al, 2013c), IL-1α (Andersson et al, 2000), IL-1β (Andersson et al, 2000; Park et al, 2003), IL-1RA (Andersson et al, 2000), IL-6 (Agnello et al, 2002; Andersson et al, 2000; Hou et al, 2011b; Kim et al, 2010b), IL-8 (Andersson et al, 2000; Dejean et al, 2012; Park et al, 2003; Treutiger et al, 2003; Wu et al, 2013c), IL-10 (Wu et al, 2013c), macrophage inflammatory protein (MIP)-1α (Andersson et al, 2000; Wu et al, 2013c), MIP-1β (Andersson et al, 2000; Wu et al, 2013c), IL-12 (Matsuoka et al, 2010), RANKL (Kim et al, 2010b), IL-11 (Kim et al, 2010b), IL-17 (Kim et al, 2010b)), chemokine (e.g., CCL5 (Pedrazzi et al, 2007), CXCL1 (Pedrazzi et al, 2007), CXCL2 (Pedrazzi et al, 2007), CCL2 (Pedrazzi et al, 2007), CCL20 (Pedrazzi et al, 2007) and CCL3 (Pedrazzi et al, 2007)), adhesion molecules (ICAM-1, VCAM-1 and E-selectin), growth factor (G-CSF (Treutiger et al, 2003)), antigen (CD40 (Matsuoka et al, 2010)) and other inflammatory associated proteins (e.g., tissue factor (TF) (Lv et al, 2009), inducible nitric oxide synthase (iNOS) (Ren et al, 2006; Sappington et al, 2002), mucin 8 (Kim e...…”

“…In addition, high-purity HMGB1 has weak pro-inflammatory activity by itself (Rouhiainen et al, 2007), but can bind with DAMP or PAMP (e.g., IL-1β (Hreggvidsdottir et al, 2009), LPS (Hreggvidsdottir et al, 2009), CpG-ODN (Hreggvidsdottir et al, 2009), Pam3CSK4 (Hreggvidsdottir et al, 2009), lipids (Rouhiainen et al, 2007), DNA or nucleosome) to amplify their pro-inflammatory activity in a synergistic manner (Table 3) (Pisetsky, 2011; Pisetsky et al, 2011). Thus, HMGB1 is an important mediator of acute lung injury (Abraham et al, 2000), brain injury (Agnello et al, 2002), islet loss (Matsuoka et al, 2010), cytoskeletal rearrangement (Wolfson et al, 2011), intestinal barrier disruption (Sappington et al, 2002), vascular barrier disruption (Wolfson et al, 2011), precancerous lesions (Dejean et al, 2012), fibrinolysis (Roussel et al, 2011), and thrombosis (Ito et al, 2007c). Inhibition of HMGB1 release and/or activity significantly decreases the inflammatory response, tissue injury, and death in animals.…”

Prediction of drug‐induced liver injury using keratinocytes

“…However, as observed in primary human keratinocytes, IL‐1β secretion via NALP3 was demonstrated in HaCaT cells (Cho et al ., ; Dai et al ., ). Furthermore, HaCaT cells express functional TLRs and RAGE (Dejean et al ., ; Pivarcsi et al ., ), which S100A8 and S100A9 bind to. These suggest that HaCaT cells can be used in evaluating the induction of S100A8, S100A9, NALP3, IL‐1β and RAGE.…”