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Interferon gamma modulates the expression of neutrophil-derived chemokines
T Kasama1, R M Strieter, N W Lukacs
1Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.
Abstract:
Specific cell recruitment to a site of acute inflammation is a crucial event characterized by the elicitation of mainly polymorphonuclear neutrophils (PMNs). Recently, it has been reported that PMNs can express and secrete chemotactic cytokines or chemokines, including IL-8, MIP-1 alpha, and MIP-1 beta. Moreover, PMN-derived chemokines are regulated by various soluble mediators, such as dexamethasone, prostaglandin E, classic chemoattractant factors (e.g., fMLP, C5a, leukotriene B4), IL-4, and IL-10. In this article we demonstrate that PMNs treated with IFN-gamma, a Th1-derived cytokine, can inhibit early mRNA expression for MIP-1 alpha, MIP-1 beta, and IL-8 (up to 8 hours post IFN-gamma addition), while augmenting their production at 24 hours post IFN-gamma addition. Furthermore, our studies demonstrate that one of the mechanisms for the activity of IFN-gamma in this system is via the autocrine activity of TNF-alpha. These data imply that PMN-derived chemokines are regulated by not only proinflammatory cytokines, including IL-1 beta and TNF-alpha, but also Th1- and Th2-derived cytokines, including IL-4, IL-10, and IFN-gamma. The role of these cytokine networks in regulating PMN-derived chemokines may play an important role in leukocyte elicitation during the initiation and maintenance of an inflammatory response.
Insights
Interferon-gamma (IFN-γ) initially suppresses polymorphonuclear neutrophil (PMN) chemokine mRNA but later boosts their production, involving tumor necrosis factor-alpha (TNF-α). This reveals complex cytokine regulation in inflammatory responses.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Polymorphonuclear neutrophils (PMNs) are key in acute inflammation.
- PMNs secrete chemokines like IL-8, MIP-1α, and MIP-1β.
- PMN chemokine production is modulated by various factors, including cytokines.
Purpose of the Study:
- To investigate the effect of Interferon-gamma (IFN-γ) on PMN-derived chemokine expression.
- To elucidate the role of tumor necrosis factor-alpha (TNF-α) in IFN-γ's activity.
Main Methods:
- Treatment of PMNs with IFN-γ.
- Analysis of mRNA expression for MIP-1α, MIP-1β, and IL-8 at different time points.
- Assessment of TNF-α involvement.
Main Results:
- IFN-γ inhibited early mRNA expression (≤8 hours) of MIP-1α, MIP-1β, and IL-8.
- IFN-γ augmented the production of these chemokines at 24 hours.
- Autocrine TNF-α activity was identified as a mechanism for IFN-γ's effects.
Conclusions:
- PMN-derived chemokines are regulated by a network of pro-inflammatory and Th1/Th2 cytokines.
- IFN-γ influences PMN chemokine regulation through both early inhibition and later augmentation.
- Cytokine networks are critical for leukocyte recruitment in inflammation.