Expression of Il-8 Gene in Human Monocytes and Lymphocytes: Differential Regulation by TNF and Il-1

Chaly, Yury; Selvan, Rathinam S.; Fegeding, Konstantin; Kolesnikova, T. S.; Voitenok, Nikolai N.

doi:10.1006/cyto.1999.0664

Cited by 28 publications

(26 citation statements)

References 27 publications

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“…Other immunomodulatory effects of ␣-defensins have been described, including a direct chemotactic activity on naive T cells and immature dendritic cells 11 as well as indirect effects mediated by up-regulation of CC-chemokine release, 26 enhanced transcription of the CXC-chemokine IL-8, 39 and increased production of proinflammatory cytokines such as TNF-␣ and IL-1␤. 40 Although the variety of molecular targets of ␣-defensins might suggest a nonspecific binding activity, we were able to demonstrate specificity both at the intramolecular and intermolecular levels. Using a panel of mAbs of defined epitope specificity, we identified selected regions of CD4 and gp120 that interact with ␣-defensins.…”

Section: Discussionmentioning

confidence: 72%

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

Furci¹,

Sironi²,

Tolazzi³

et al. 2006

Blood

102

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␣-defensins are antibiotic peptides that act as natural inhibitors of HIV-1 infection. However, the mechanisms of such inhibition are still unclear. Here we demonstrate that ␣-defensins block the earliest steps in the viral infectious cycle, as documented using an HIV-1 envelopemediated cell-fusion assay. A broad-spectrum inhibitory activity was observed on primary and laboratory-adapted HIV-1 isolates irrespective of their coreceptor specificity and genetic subtype. A primary mechanism of such inhibition was identified as the ability of ␣-defensins to bind specifically both to the primary HIV-1 cellular receptor, CD4, and to the viral envelope glycoprotein, gp120. Moreover, treatment of CD4 ؉ T cells with ␣-defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with ␣-defensins were mapped to the D1 domain of CD4 and to a surface contiguous to the CD4-and coreceptorbinding sites of gp120. Consistent with these findings, ␣-defensins inhibited the binding of gp120 to CD4. These data demonstrate that ␣-defensins specifically block the initial phase of the HIV infectious cycle and modulate the expression of CD4, a critical receptor in the physiology of T-cell activation. IntroductionEvidence suggests that a concerted action of innate and adaptive immune responses is essential for the effective containment and, ultimately, the clearance of invading microorganisms. 1 The innate immune system is phylogenetically more archaic and constitutes the first line of antimicrobial defense, characterized by a rapid response time; however, it is limited in its target specificity. By contrast, the adaptive immune system has evolved refined molecular devices for the recognition of a wide variety of specific epitopes, but a lag time is required for its functional activation. Once activated, most of the cells involved in both innate and cognate immune responses secrete soluble factors, including cytokines, chemokines, antibiotic peptides, and others, which can directly antagonize infectious microorganisms and/or contribute to the recruitment and activation of other immune cells, thereby amplifying the cascade of defense mechanisms and bolstering their effectiveness. 2,3 In HIV infection, various host-derived soluble factors with antiviral activity have been described, which act by both specific and nonspecific mechanisms. These include chemokines such as RANTES, MIP-1␣, and MIP-1␤ 4 ; cytokines such as the interferons, IL-10, IL-13, IL-16, transforming growth factor-␤, and others 5 ; as well as, more recently, defensins. [6][7][8][9] Defensins are natural antibiotic peptides that play an important role in innate immune responses by acting as broad-spectrum antibacterial, antifungal, and antiviral effector molecules 10 as well as by enhancing certain adaptive immune responses. 11 ␣-defensins 1 to 3 are 3-to 4-kDa cationic peptides (29 to 30 amino acids [aa]) characterized by a conserved 6-cysteine motif, with 3 disulfide bonds that impose a characteristic ␤-sheet ...

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Section: Discussionmentioning

confidence: 72%

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

Furci¹,

Sironi²,

Tolazzi³

et al. 2006

Blood

102

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“…NF-kB-mediated induction of IL-8 as a well-established model (7)(8)(9) to investigate mechanisms underlying the modulation of NFkB by opioids in T cells. At first glance, the effects of opioids on the transcription factor appear to be similar in the T cells and the neuronal cells.…”

Section: Discussionmentioning

confidence: 99%

“…Many effects mediated by NF-kB are proinflammatory, for example, the induction of the cytokine IL-8 (7)(8)(9). Several observations suggest that modulation of NF-kB is one of the mechanisms underlying the modulatory effects of opioids.…”

mentioning

confidence: 99%

Inhibition of NF-κB by Opioids in T Cells

Börner

Kraus

2013

The Journal of Immunology

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Opioids potently inhibit a number of physiological and pathophysiological effects such as pain and inflammation in the brain and the periphery. One of the targets of opioids mediating such effects is the proinflammatory transcription factor NF-κB. In neuronal cells, opioids inhibit this factor by inducing I-κB independently on calcium, involving the opioid-mediated activation of the transcription factor AP-1. However, when and how precisely NF-κB is modulated by opioids in T cells are unknown. By using the TNF-triggered, NF-κB–mediated induction of IL-8 mRNA in primary human T cells and Jurkat T cells, in this study we show that opioids inhibit NF-κB in T cells as well, but that the underlying mechanisms are different from those observed in neuronal cells. We found that stimulation of the T cells with opioids resulted in a significant inhibition of the TNF-triggered ubiquitination and degradation of I-κB. Additionally, an opioid-mediated induction of the deubiquitinating enzyme ubiquitin-specific protease 15 was observed, which is known to inhibit the NF-κB pathway by stabilizing I-κB. The induction of ubiquitin-specific protease 15 was dependent on calcium and the transcription factor NFAT. Activation of AP-1 and induction of I-κB in response to the opioids were not observed in the T cells. These results indicate that μ opioid receptors, which mediate the effects in both cell types, might be coupled to different effector cascades in the different cell types, which may then result in cell type–specific effects of the drugs.

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“…The serum concentration of TNF-␣ and IL-8 is associated with the severity of diseases and the outcome of the patients in many inflammatory/infectious processes [11,12]. TNF-␣, the major mediator of the acute inflammatory response, is important in the activation of endothelial cells and in the expression of adhesive molecules for leukocyte integrins and endothelial selectins.…”

mentioning

confidence: 99%

Hyperresponsiveness of neutrophils from gp 91phox deficient patients to lipopolysaccharide and serum amyloid A

et al. 2004

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Expression of Il-8 Gene in Human Monocytes and Lymphocytes: Differential Regulation by TNF and Il-1

Cited by 28 publications

References 27 publications

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

Inhibition of NF-κB by Opioids in T Cells

Hyperresponsiveness of neutrophils from gp 91phox deficient patients to lipopolysaccharide and serum amyloid A

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