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Interleukin-12 Attenuates Pulmonary Fibrosis via Induction of Interferon-γ* FREE TO VIEW

Michael P. Keane, MD, FCCP; John A. Belperio, MD; Marie D. Burdick; Robert M. Strieter, MD, FCCP
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*From the Division of Pulmonary and Critical Care Medicine (Drs. Keane, Belperio, Burdick, and Strieter), UCLA School of Medicine, Los Angeles, CA.

Correspondence to: Michael P. Keane, MD, FCCP, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine 14-154 Warren Hall, 900 Veteran Ave, Los Angeles, CA 90095-1922.

Chest. 2001;120(1_suppl):S8. doi:10.1378/chest.120.1_suppl.S8
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Few studies have addressed the importance of vascular remodeling in the lung during the development of bleomycin-induced pulmonary fibrosis (BPF). Lung-derived angiogenic activity is increased in bleomycin-treated mice as compared to saline solution-treated control mice. Moreover, we have shown that the CXC chemokines, macrophage in inflammatory protein-2 and macrophage in inflammatory protein-2 and interferon (IFN)-inducible protein 10 (IP-10), have an important role in the pathogenesis of BPF that is mediated via the regulation of angiogenesis. Interleukin (IL)-12 is a potent inducer of IFN-γ and hence the angiostatic CXC chemokines, IP-10 and monokine induced by IFN-γ (MIG). We postulated that interleukin (IL)-12 would attenuate BPF via inhibition of angiogenesis. To test this hypothesis, we administered IL-12 or human serum albumin to bleomycin-treated CBA/J mice, by daily intraperitoneal injection until day 12. Mice treated with IL-12 demonstrated decreased hydroxyproline levels as compared to human serum albumin-treated control mice (24.2 ± 1.4 vs 30.8 ± 2.5; p < 0.05). Furthermore, administration of IL-12 led to a time-dependent increase in lung IFN-γ, IP-10, and MIG. The antifibrotic effect of IL-12 could be attenuated with simultaneous administration of neutralizing anti-IFN-γ antibodies. These findings support the notion that the antifibrotic effects of IL-12 are mediated through IFN-γ and subsequently IP-10 and MIG.

Abbreviations: BPF = bleomycin-induced pulmonary fibrosis; IFN = interferon; IL = interleukin; IP-10 = interferon-inducible 10 protein 10; MIG = monokine induced by interferon-γ

Supported by National Institutes of Health grants HLO3906, P50HL56402, and P50HL6028.

Dr. Belperio is the recipient of a Glaxo Wellcome fellowship award.




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