Interferon‐γ limits Th1 lymphocyte adhesion to inflamed endothelium: A nitric oxide regulatory feedback mechanism

Abstract

AustraliaCD4 + T helper (Th1 and Th2) cell localization to a site of inflammation is important for the development, maintenance and regulation of an immune response. The factors that regulate Th1 and Th2 cell recruitment into tissue are not fully understood. The aim of the present study was to examine the effect of different cytokine microenvironments on the recruitment of Th1 and Th2 lymphocytes into tissue. Fluorescently labelled Th1 or Th2 lymphocyte-endothelial interactions were observed via intravital microscopy of the cytokine-treated cremaster muscle. Our results show that TNF-a alone is sufficient to maximally recruit Th1 cells. Surprisingly, treatment with TNF-a + IFN-c significantly decreased Th1 adhesion and emigration in comparison to TNF-a treatment alone. The decreased adhesion of Th1 cells in response to TNF-a + IFN-c reflected a decreased ability to bind to ICAM-1 and was iNOS-dependent. This phenomenon was not observed with Th2 cells. These results suggest that IFN-c may play a key immunomodulatory role in the recruitment of different T lymphocyte subsets. Indeed, blockade of IFN-c or iNOS function during the Th1-mediated contact hypersensitivity response resulted in an acceleration and exacerbation of the late-phase inflammatory response.

Amitriptyline and Acute Inflammation: A Study Using Intravital Microscopy and the Carrageenan-Induced Paw Edema Model

“…Obuchowicz et al [36] showed the ability of amitriptyline to decrease the production of IL-1 ␤ and TNF-␣ in glial cell cultures of rats. Thus, taken together, the literature and the present data suggest that amitriptyline effects on leukocyte behavior might be attributable to the ability of antidepressants to decrease proinflammatory cytokines and, consequently, adhesion molecule expression and/or affinity by their ligands [37] . In fact, data from our laboratory (data not shown) confirm the ability of amitriptyline to reduce TNF-␣ and IL-1 ␤ levels in the serum of rats.…”

Lymph node vascular plasticity during Herpes Simplex Virus Type II infection.

“…Based on the previously established importance of eNOS in regulating cell migration, vascular growth, endothelial ccll proliferation, and modulation of VEGF in other contexts (Bcnest et al, 2008, Chyou et al, 2008, Norman et al, 2008, Yu et a!., 2005, the role of eNOS in arteriole remodeling was investigated. Genetic ablation of models lacking expression of eNOS showed an inability to remodel LN arterioles in response to infection ( Figure 13A, B).…”

“…This suggests that exogenous supply of L-arginine may be useful in increasing the bioavailability of NO in states of adverse immune reaction and could potentially be used to aid NO production and inhibit lymphocyte adhesion. Additionally, recent studies provide evidence that NO may also promote lymphocyte transmigration through stimulation from ICAM-1 (Martinelli et al, 2009) with the ability of some leukocyte subsets to bind ICAM-1 and mediate adhesion demonstrated to be NO dependent (Norman et al, 2008).…”

“…In skeletal muscle, TNF-alpha recruits Tul cells (Norman et al, 2008) and in aging models of delayed hypersensitivity, memory CD4* T cells arc prevented from migrating due to a lack of TNF-alpha secretion (Agius et al, 2009). TNF-alpha has been shown to be an inducer of vascular remodeling acting through TNF receptors on vascular ECs during infection, as well as a mediator of angiogenesis in vivo, and an inducer of NOS during HSV infection (Baluk et al, 2009, Benecia, et al, 2003, Frater-Schrodcr et al, 1987, Leibovich et al, 1987.…”

Papel do antidepressivo amitriptilina sobre a resposta inflamatória aguda em ratos

“…Os autores sugeriram que teria ocorrido uma alteração conformacional ou de afinidade das moléculas de adesão, e não em sua expressão, o que justificaria os achados (NORMAN et al, 2008). Ou seja, a não observância de alterações na expressão de moléculas de adesão por leucócitos de animais tratados com amitriptilina no presente trabalho poderia ter sido decorrência de uma alteração na conformação ou afinidade dessas moléculas.…”