Glucocorticoid-attenuated response genes encode intercellular mediators, including a new C-X-C chemokine

Area of Science:

• Molecular Biology
• Immunology
• Genetics

Background:

• Glucocorticoids possess anti-inflammatory properties primarily by inhibiting the induction of genes encoding intercellular mediators like cytokines.
• It was hypothesized that a specific class of genes, termed glucocorticoid-attenuated response genes (GARGs), are induced by inflammatory stimuli and involved in paracrine functions.

Purpose of the Study:

• To identify and characterize immediate-early/primary response genes whose induction is suppressed by glucocorticoids.
• To investigate the function of the products of these GARGs, particularly in intercellular communication and inflammatory processes.

Main Methods:

• Construction of a lambda cDNA library from murine Swiss 3T3 cells stimulated with lipopolysaccharide (LPS) or serum in the presence of cycloheximide.
• Differential hybridization screening of 15,000 plaques to identify LPS-induced and dexamethasone-attenuated cDNAs.
• Sequence analysis of cloned cDNAs to identify known and novel genes, including chemokine family members.

Main Results:

• Twelve LPS-induced, dexamethasone-attenuated cDNAs were cloned; seven were previously known, encoding intercellular mediators.
• A novel CXC chemokine, designated LIX (LPS-induced CXC chemokine), was identified among the previously unknown GARGs.
• Analysis revealed significant sequence homology in the 3'-untranslated regions of LIX and other CXC chemokines, suggesting a potential regulatory role.

Conclusions:

• A significant proportion of GARGs encode intercellular mediators, supporting the initial hypothesis.
• LIX is a novel chemokine induced by LPS in fibroblasts, potentially playing a role in recruiting inflammatory cells to sites of injury or infection.
• Unusual sequence conservation in the 3'-untranslated regions of certain chemokines warrants further investigation into their regulatory functions.