Type I immune response cytokine-chemokine cascade is associated with pulmonary arterial hypertension

Division of Pulmonary, Critical-Care, Allergy & Immunology
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation (Impact Factor: 6.65). 05/2012; 31(8):865-73. DOI: 10.1016/j.healun.2012.04.008
Source: PubMed


Perivascular infiltrating mononuclear cells have been described in the vasculopathy found in multiple types of pulmonary arterial hypertension (PAH). We determined the expression of a specific type 1 immune response cytokine-chemokine cascade-interleukin (IL)-18 → (monokine induced by γ-interferon [MIG]/chemokine [C-X-C motif] ligand [CXCL] 9, interferon γ-induced protein [IP]-10/CXCL10 and interferon-inducible T-cell α chemoattractant [ITAC]/CXCL11)-in plasma samples from individuals with World Health Organization (WHO) Group 1 PAH.
We analyzed cytokine and chemokine protein levels in plasma from 43 individuals with WHO Group 1 PAH by enzyme-linked immunosorbent assay compared with 35 healthy individuals. Immunohistochemical studies on tissue specimens from WHO Group 1 PAH patients were performed for cytokines and chemokines and their respective receptors.
Plasma IL-18 levels from WHO Group 1 PAH patients were significantly increased compared with healthy controls. Downstream chemokine CXCL10, but not CXCL9 or CXCL11, was markedly elevated compared with controls. Cellular sources of IL-18 were medial but not intimal smooth muscle cells. IL-18Rα was expressed from medial smooth muscle cells, endothelial cells, and mononuclear cells. CXCL10 and its main receptor, CXCR3, were expressed from infiltrating vascular wall mononuclear cells.
These data suggest that augmented expression of IL-18 and CXCL10 may perpetuate an inflammatory milieu that eventually contributes to the vascular obstruction characteristic of PAH.

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    • "LIX facilitates neutrophil recruitment which can promote oxidative stress induced damages [36]. Similarly, MIG is another overexpressed, effective chemo-attractant for mononuclear cells from the CXC chemokine group which can also contribute to cell death [37]. MIP chemokines released from macrophages activate granulocytes and lymphocytes and enhance the synthesis of proinflammatory cytokines such as IL-1, IL-6 and tumor necrosis factor (TNF)-α, which play a crucial role in the pathomechanism of PH. "
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    PLoS ONE 08/2014; 9(8):e104890. DOI:10.1371/journal.pone.0104890 · 3.23 Impact Factor
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    • "IL-18, a pro-inflammatory cytokine and member of the IL-1 family, is activated by the cleavage of IL-1β–converting enzyme, generating the biologically active IL-18. IL-18 is elevated in the patients with PAH and there is evidence that abnormal levels of IL-18 play a role in vasculopathy of the pulmonary circulation [29]. A recent study demonstrated that vascular injury may lead to an upregulation of IL-18 from PASMC of the medial vessel layer. "
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    Respiratory research 04/2014; 15(1):47. DOI:10.1186/1465-9921-15-47 · 3.09 Impact Factor
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