Pivotal role of TARC, a CC chemokine, in bacteria-induced fulminant hepatic failure in mice.

Abstract

Thymus and activation-regulated chemokine (TARC) is a recently identified lymphocyte-directed CC chemokine which specifically chemoattracts T helper type 2 CD4 ϩ T cells in human. To establish the pathophysiological roles of TARC in vivo, we investigated whether a monoclonal antibody (mAb) against TARC could inhibit the induction of hepatic lesions in murine model using Propionibacterium acnes and lipopolysaccharide (LPS). P . acnes -induced intrahepatic granuloma formation in the priming phase is essential to the subsequent liver injury elicited by a low dose of LPS.The priming phase appears to be dominated by Th1 type immune responses determined by the profile of chemokine and chemokine receptor expression. TARC was selectively produced by granuloma-forming cells, and CC chemokine receptor 4 (CCR4)-expressing CD4 ϩ T cells migrated into the liver after LPS administration. In vivo injection of anti-TARC mAb just before LPS administration protected the mice from acute lethal liver damage, which was accompanied by a significant reduction of both CCR4 mRNA expression and IL-4 production by liver-infiltrating CD4 ϩ T cells. Moreover, both TNF-␣ and Fas ligand expressions in the liver were decreased by anti-TARC treatment. These results suggest that recruitment of IL-4-producing CCR4 ϩ CD4ϩ T cells by granuloma-derived TARC into the liver parenchyma may be a key cause of massive liver injury after systemic LPS administration. ( J. Clin. Invest. 1998Invest. . 102: 1933Invest. -1941

Chemokine Expression Dynamics in Mycobacterial (Type-1) and Schistosomal (Type-2) Antigen-Elicited Pulmonary Granuloma Formation

“…It is a CCR4 ligand that attracts primed CD4 ϩ T cells, 64 in particular IL-4-producing T cells. 65 Interestingly, TARC is up-regulated by both IL-4 and IFN-␥ in bronchial epithelial cells, and a maximum production occurred with combination of TNF-␣, IL-4, and IFN-␥. 66 Our findings now suggest a common role in granuloma formation.…”

Development of Atopic Dermatitis-Like Skin Lesions in STAT6-Deficient NC/Nga Mice

“…The expression profile of chemokines in the skin lesion showed increased expression of TARC, eotaxin 2, and CC chemokine receptors even in STAT6 Ϫ/Ϫ NC mice. The TARC/MDC-CCR4 system has been shown to be involved in the Th2-mediated disease process (37,38). However, consistent with the observation in NC mice that IFN-␥, but not IL-4, induces TARC expression in keratinocytes (15), our results indicate that the enhancement of TARC expression at the pathological site correlated with the increased IFN-␥ expression.…”

“…Moreover, recent reports demonstrated that transgenic mice expressing caspase 1 in keratinocytes spontaneously developed AD-like skin disease with an elevation of the active form of IL-18 in serum (37). Recent linkage analysis demonstrated that the locus responsible for skin disease in NC mice is on chromosome 9, and the IL-18 gene is near the locus (42).…”

Intervention of Thymus and Activation-Regulated Chemokine Attenuates the Development of Allergic Airway Inflammation and Hyperresponsiveness in Mice

“…Hamster anti-mouse TARC mAb 5H5 was prepared as described previously (23,24). The specificity of this Ab was evaluated by 1) binding assay using ELISA, 2) calcium mobilization assay, and 3) chemotaxis assay as described below.…”