Lawlor KE, Wong PKK, Campbell IK, van Rooijen N, Wicks IP. Acute CD4+ T lymphocyte-dependent interleukin-1-driven arthritis selectively requires interleukin-2 and interleukin-4, joint macrophages, granulocyte-macrophage colony-stimulating factor, interleukin-6, and leukemia inhibitory factor. Arthritis & Rheumatism. 2005 Dec;52(12):3749–54.

Abstract

Objective. To further investigate the effects of interleukin-1 (IL-1) in immune-mediated joint inflammation, we examined the role of IL-2, Th1 interferon-γ (IFNγ), and Th2 (IL-4) cytokines, joint macrophages, and macrophage-derived cytokines (IL-12 p40, IL-6, leukemia inhibitory factor [LIF], oncostatin M [OSM], and granulocyte–macrophage colony-stimulating factor [GM-CSF]) in a CD4 T lymphocyte–dependent model of acute arthritis.

Methods. Methylated bovine serum albumin (mBSA)/IL-1–induced arthritis was elicited in wild-type, gene-knockout, and monoclonal antibody–treated mice. Synovial lining macrophages were selectively depleted by intraarticular injection of clodronate liposomes prior to disease induction. The severity of arthritis was assessed histologically.

Results. Mice deficient in IL-2 were almost completely protected from arthritis, and neutralization of IL-4 reduced the severity of disease. In contrast, arthritis severity and resolution appeared to be independent of IFN. Synovial lining macrophage depletion markedly reduced arthritis severity. IL-6 or LIF deficiency was only modestly protective, although as previously reported, GM-CSF deficiency conferred profound disease resistance. IL-12 p40–deficient mice (which lack IL-12 and IL-23) and OSM receptor–deficient mice were susceptible to mBSA/IL-1–induced arthritis.

Conclusion. Acute mBSA/IL-1–induced arthritis is dependent on IL-2 and IL-4, but not IFNγ. In vivo, the Th1/Th2 paradigm may be distorted by the presence of macrophage-derived cytokines such as IL-1. Synovial lining macrophages are essential in mBSA/IL-1–induced arthritis. However, the requirement for macrophage-derived cytokines is selective; that is, IL-6, LIF, and especially GM-CSF are necessary, but IL-12, IL-23, and OSM are dispensable. IL-1 may therefore influence both adaptive and innate immune mechanisms in acute inflammatory arthritis.

Clodronate Concentration Total Lipid Concentration Lipid Composition Lipid Mole % Liposome Type Control Liposomes Control Free Clodronate
5 mg/ml 23.5 mg/ml EPC/chol 84/16 MLV none ND
 
Animal Description Clodronate Dose Dosing Method/Site Target Phagocytes Systemic Dosing? Systemic Results
C57BL/6, DBA/1, male, 8-12 w 42 µg/10 µl intra-articular/knee synovial no N/A

Notes

  1. Liposome prep method cited—
    van Lent PLEM, Holthuysen AEM, van den Bersselaar LAM, van Rooijen N, Joosten LAB, van de Loo FAJ, et al. Phagocytic lining cells determine local expression of inflammation in type II collagen–induced arthritis. Arthritis & Rheumatism. 1996 Sep;39(9):1545–55.
  2. Experimental timeline

    Mice were given intra-articular injections of clodronate liposomes in one knee while PBS was injected into the contralateral knee 7 d and 4 d prior to induction of arthritis.

  3. 7 d post-first liposome treatment, at the time of maximal macrophage depletion, 2 mg in 10 µl methylated BSA was dosed intra-articularly followed by s.c. injection of 0.25 µg human IL-1β in 20 µl into the hindpaw of the same limb.
  4. The human IL-1β was dosed on days 8 and 9 as well.
  5. Mice were sacrificed 7d post-induction of arthritis and assessed histologically for disease severity.

Results

  1. The authors report a 75% reduction in histological score for disease severity in clodronate-liposome depleted animals compared to controls.
  2. No other experiments related to clodronate liposomes reported in this paper.