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IL-12 and IL-18 Are Increased and Stimulate IFN- Production in Sarcoid Lungs

Katsunori Shigehara^*,,, Noriharu Shijubo^1,, Mitsuhide Ohmichi, Ryuji Takahashi, Shin-ichiro Kon, Haruki Okamura^¶, Masashi Kurimoto^||, Yohmei Hiraga, Tachio Tatsuno^*, Shosaku Abe and Noriyuki Sato

^* Hokkaido Branch of Japan Anti-Tuberculosis Association, Sapporo, Japan; Third Department of Internal Medicine and First Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Respiratory Disease, Sapporo Hospital, Hokkaido Railway Co. Sapporo, Japan; ^¶ Laboratory of Host Defense, Institute for Advanced Medical Sciences, Hyogo Medical College, Nishinomiya, Japan; and ^|| Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan

Sarcoidosis is a systemic chronic granulomatous disease of unknown cause. Recent investigations revealed that the cytokine profile in inflamed lesions of sarcoidosis is Th1 dominant. To obtain better immunopathologic understanding of sarcoidosis, we examined the expression of IL-12 and IL-18 and their roles in IFN- production in pulmonary sarcoidosis. Sarcoid cases had significantly elevated levels of IL-12 (p40 and p70) and IL-18 in bronchoalveolar lavage (BAL) fluids compared with healthy subjects. IL-12 p70 and IL-18 were immunohistochemically expressed in the epithelioid cells and giant cells of sarcoid granulomas. Significant induction of IFN-, IL-12 p70, and IL-18 was observed from sarcoid BAL fluid cells with LPS stimulation, whereas LPS tended to induce only IL-12 p70 in BAL fluid cells from healthy subjects. Sarcoid cases had significantly greater IFN- induction with LPS stimulation than healthy subjects did. IL-18 mRNA expression was observed in freshly isolated sarcoid BAL fluid cells as well as in LPS-stimulated sarcoid BAL fluid cells, but IFN- and IL-12 mRNA expression was observed only in LPS-stimulated BAL fluid cells. Treatment with anti-IL-12- and anti-IL-18-neutralizing Abs significantly inhibited IFN- production from LPS-stimulated BAL fluid cells of sarcoid cases. Coadministration of rIL-12 or rIL-18 induced greater IFN- production in sarcoid BAL fluid cells than in normal BAL fluid cells. We concluded that bioactive IL-12 and IL-18 were produced in sarcoid BAL fluid cells and synergistically induced IFN- production, indicating important cytokines in the Th1 response of sarcoidosis.

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