Th1 and Th2 cytokines exert regulatory effects upon islet microvascular areas in the NOD mouse.
In this study, we show that intra- and peri-islet microvascular areas undergo different changes during the islet inflammation in the nonobese diabetes-prone female mice. Actually, although the islet vascular area (IVA) considerably decreases while the infiltration progresses, at 15 weeks of age, the peri-islet vascular bed is unexpectedly and significantly increased. On the contrary, the intra-IVA is significantly decreased, due to vessel dilation. Later, by 20-25 weeks of age, a decrease of both IVA occur, due to a significant islet beta cell loss. Moreover, a dramatic fall of natural free radical scavenger values, which, in turn, exert an influence upon vessels, is observed. These effects are completely counteracted by the administration of IL-4, a Th2 protective cytokine; IL-10, another putative Th2 cytokine, exerts direct effects upon endothelial cell (EC) function, as shown by the increase of endothelial nitric oxide synthase (eNOS) mRNA transcripts and by the release of endothelial NO which, in turn, exert vasodilatory effects; moreover, this cytokine significantly upregulates adhesion molecules on endothelia. On the other hand, IL-1beta, a Th1 proinflammatory cytokine, dramatically increases nitrite and nitrate levels, as well as inducible nitric oxide synthase (iNOS) transcripts and also upregulates islet ICAM-1 expression as well as circulating ICAM-1 levels. Taken together, our findings clearly show that cytokines and islet endothelia are directly involved in the pathophysiology of the disease. Their reciprocal influence gives new insight to understand the role of microvasculature during islet beta cell attack.
Papaccio
Gianpaolo
G
Department of Experimental Medicine, Laboratory of Histology and Embryology, School of Medicine, Second University of Naples, 5 via Luciano Armanni, 80138 Naples, Italy. gianpaolo.papaccio@unina2.it
Pisanti
Francesco Aurelio
FA
Montefiano
Rosita Di
RD
Graziano
Antonio
A
Latronico
Michael V G
MV
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D018929:Cell Culture Techniques; D016207:Cytokines / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology; D007515:Islets of Langerhans / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008833:Microcirculation / Q000502:physiology; D008853:Microscopy / Q000379:methods; D009566:Nitrates / Q000032:analysis; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000032:analysis; D010088:Oxidoreductases / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism*; D013997:Time Factors
D001786:Blood Glucose; D016207:Cytokines; D007378:Interleukins; D009566:Nitrates; D009573:Nitrites; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D012313:RNA; D010088:Oxidoreductases