Role of interleukin-6 in a glucan-induced model of granulomatous vasculitis Shannon D. McClintock a , Adam G. Barron a , Eric W. Olle a , Michael P. Deogracias a , Roscoe L. Warner a , Mark R. Opp b , Kent J. Johnson a, ⁎ a Department of Pathology, University of Michigan Medical School, 7520 MSRB I, 1301 Catherine Rd., Ann Arbor, MI 48109, USA b Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA Received 6 July 2006 Available online 12 January 2007 Abstract The role of interleukin-6 (IL-6) in granulomatous vasculitis is not well understood. To investigate its involvement in this type of vasculitis a model of glucan-induced pulmonary vasculitis employed interleukin-6 deficient (IL-6 -/- ) mice. Briefly, IL-6 -/- mice and C57B/J6 wild type (IL-6 +/+ ) mice were injected intravenously with a suspension of glucan isolated from the cell wall of bakers yeast which results in a granulomatous vasculitis primarily in the pulmonary vasculature. Histological examination demonstrated no significant difference in the number of infiltrating leukocytes between the IL-6 +/+ and IL-6 -/- glucan-injured mice. Similar numbers of granulomas were noted in both the IL-6 +/+ and IL-6 -/- injured animals, while no granulomas were seen in saline injected control mice. Cells recovered from the bronchoalveolar lavage (BAL) fluid were differentially stained and counted. While there was a significant increase in infiltrating leukocytes recovered from the BAL following glucan-induced injury, there was no significant difference between the IL-6 +/+ and IL-6 -/- mice. In addition, no difference was demonstrated in total protein content in the BAL fluid between IL-6 +/+ and IL-6 -/- mice. However, myeloperoxidase (MPO) activity in the lungs of the IL-6 -/- mice was less than in their IL-6 +/+ counterparts suggesting that these animals have a partial defect in their ability to recruit neutrophils in this model. Studies done to look for levels of other cytokines/chemokines in these animals to compensate for the loss of IL-6 revealed that only IL-10 in the sera (p < 0.016) and BAL fluid (p < 0.05) of IL-6 -/- mice was significantly higher then their IL-6 +/+ -injured counterparts. These studies suggest that IL-6, while possibly involved in early neutrophil accumulation in this model does not appear critical to the development of the TH-2 mediated granulomatous vasculitis. © 2006 Elsevier Inc. All rights reserved. Keywords: Wegener's; IL-6 K.O.; Vasculitis; Granulomatous Introduction Wegener's granulomatosis (WG) is an idiopathic systemic vasculitis with a broad clinical spectrum. This disease is manifested primarily in the upper and lower respiratory tract, kidneys, and skin (Harman and Margo, 1998). It is characterized histologically by primarily vascular granulomatous involve- ment and may be associated with fibrinoid necrosis (Travis et al., 1991). In the kidney, WG is also associated with a glomerulonephritis and is actually one of the leading causes of crescentic glomerulonephritis (Langford et al., 2000). While the underlying cause of the disease is unknown, the utilization of assays to measure neutrophil cytoplasmic antibodies (ANCA) in the serum of these patients has revolutionized the diagnosis of this disease with these patients characteristically having antibodies against the neutrophil granule enzyme proteinase 3 (pANCA; Pettersson and Heigl, 1992). Immune mediators such as cytokines/chemokines, cell surface antigens and adhesion molecules have been assessed in patients with vasculitis. In patients with WG, assessment of blood mononuclear cells has found evidence of a TH-1 type immune response with primarily CD4 + T cells producing IFN- γ, IL-12 and TNF-α (Komocsi et al., 2002; Ludviksson et al., 1998; Schlesier et al., 1995). In studies which looked at cytokines upregulated in the plasma of patients with vasculitis, including WG, there is evidence of increased levels of IL-6 as well as other cytokines (Murakozy et al., 2001). In addition, some of these studies have suggested that circulating IL-6 levels correlate with the severity of the vascular lesions whereas other studies do not (Mihara and Ohsugi, 1990; Horii et al., 1989; Gordon et al., 1991). Experimental and Molecular Pathology 82 (2007) 203 – 209 www.elsevier.com/locate/yexmp ⁎ Corresponding author. Fax: +1 734 764 4308. E-mail address: kjjkjj@umich.edu (K.J. Johnson). 0014-4800/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yexmp.2006.07.003