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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Division of Pulmonary, Critical-Care, Allergy & Immunology; David Geffen School of Medicine, Ronald Reagan-University of California Los Angeles Medical Center, CA 90095, USA. dross@mednet.ucla.edu
David J
DJ
Ross
Robert M
RM
Strieter
Michael C
MC
Fishbein
Abbas
A
Ardehali
John A
JA
Belperio
D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D007113:Immunity, Innate / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D014944:World Health Organization
C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D016207:Cytokines; D020382:Interleukin-18; D054367:Receptors, CXCR3; D053724:Receptors, Interleukin-18