Fibroblast Like Synoviocytes by repression of IL-6, COX-2and GM-CSF mRNA levels as well as of IL-6 proteinproduction. In sharp contrast to DEX, CpdA did notstimulate gene expression from GRE-driven genes, likehPAP and SGK. The in vivo capacity to suppress inflam-mation was studied in the Collagen Induced Arthritismodel. Clinical disease severity was assessed by scoringthe number of affected joints and the degree of jointswelling. CpdA dosed at 12 mg/kg markedly reducedclinical severity compared to the PBS control group andlikewise, the number of histologically affected knee jointswas significantly lower in the CpdA treated group. The invivo presence of transactivation was determined bymeasuring glycemia. Administration of DEX increasedglycemia compared to PBS, whereas administration ofCpdA did not. These findings indicate that CpdA may bea lead compound of a novel class of anti-inflammatoryagents with fully dissociated properties and might thushold great potential for therapeutic use.

doi:10.1016/j.clim.2006.04.069

F.30. Abrogation of Established InflammatoryArthritis By Honokiol: Gaba(a)-Mediated Alterationof CD40 and LMP1 Signaling in B-Cells.Melissa Munroe, Gail Bishop. Microbiology, InternalMedicine, and VAMC, University of Iowa, Iowa City, IA.

Our lab has extensively studied signaling in B-cells byCD40 and its Epstein Barr viral mimic, LMP1. Honokiol(HNK), a phenolic compound isolated and purified frommagnolia, has been found to have a number of pharma-cologic benefits, including anxiolytic and anti-neoplasticproperties, without the toxicity found in vivo withcurrent treatments. We examined the ability of HNK toabrogate the inflammatory mouse model of rheumatoidarthritis, collagen induced arthritis (CIA). HNK, given at 3mg/day ip, diminished the severity of established CIA tobaseline levels in both CD40-LMP1 transgenic mice andtheir congenic C57BL/6 counterparts, as measured bypaw swelling and clinical scores. Ex vivo studies fromthese mice revealed diminished CD40 or CD40-LMP1mediated TNF-a and IL-6 production by splenic B-cellsfrom mice receiving HNK. We evaluated potential molec-ular mechanisms leading to the anti-inflammatory effectsof HNK using B-cell lines expressing either hCD40 or thehCD40-LMP1 chimeric receptor. CD40 and LMP1 mediatedNFnB and JNK pathways were abrogated, but noteliminated by HNK, with a dose-dependent decrease inTNF-a and IL-6 production without significant cell death.Furthermore, the anti-inflammatory effects of HNK couldbe reversed using GABA inhibitors, a previously reportedtarget for HNK interaction. These findings are particularlyexciting and suggest that the nontoxic anti-inflammatoryproperties of HNK could be a means for blocking theautoimmune response without altering general immunefunction.

doi:10.1016/j.clim.2006.04.070

F.31. L-Type Voltage-Gated Ca2+ Channels in CD4+

T-Cells.Candace Cham,1 Li-Fen Lee,2 Hugh McDevitt.3 1Program inImmunology, Stanford University, Stanford, CA;2Department of Microbiology & Immunology, StanfordUniversity, Stanford, CA; 3Departments of Medicine andMicrobiology & Immunology, Stanford University, Stanford,CA.

All available evidence has indicated that calcium (Ca2+)-release activated Ca2+ (CRAC) channels are the only Ca2+

channels responsible for Ca2+ influx into T-cells following T-cell activation. However, several groups have recentlyreported that L-type voltage-gated Ca2+ channels (VGCCs)are expressed in T-cells and may be functional. In a genearray experiment studying the effects of a 3-week treatmentof tumor necrosis factor alpha (TNF) in BDC2.5 transgenicnonobese diabetic (NOD) mice, expression of the L-type VGCCsubunit Cav1.3 was reduced by 2-fold and h3 subunit wasreduced by 4-fold. This led us to examine whether these andother VGCC subunits are expressed in NOD CD4+ T-cells.Expression of Cav1.2, Cav1.3, h1, and h3 subunits of L-typeVGCCs was detected in purified NOD CD4+ T-cells by RT-PCR.Cav1.2, Cav1.3, and h3 subunit proteins were found in JurkatT-cells, but are truncated (Stokes, et al. 2004. J Biol Chem.279(19):19566-73). In addition, two truncated isoforms ofCav1.4 subunit protein are detected in human T lymphocytes(Kotturi and Jefferies. 2005. Mol Immunol. 42(12): 1461-74).Since the truncated forms of Cav1.4 lack critical voltage-sensing domains, it is hypothesized that these channels maynot be voltage-gated. Together, these data suggest: 1) L-typeVGCCs may contribute to overall Ca2+ mobilization during T-cell activation, and 2) L-type VGCCs in lymphocytes may notbe regulated by changes in membrane potential. Furthercharacterization of other subunits and proteomic studies areunderway to investigate the importance of L-type VGCCs inCD4+ T-cell activation.

doi:10.1016/j.clim.2006.04.071

F.32. Is Upregulation of IL-17 Necessary forExpression of Arthritis in IFN-;-Deficient Mice?Cong-Qiu Chu, Keith Elkon. Division of Rheumatology,University of Washington, Seattle, WA.

Rheumatoid arthritis (RA) is considered to be a Th1-mediated disease. However, the role of interferon-g (IFN-g),the prototypic Th1 cytokine, in the pathogenesis of RA hasbeen questioned since little IFN-g is present in RA joints.Studies using IFN-g or IFN-g receptor knockout (KO) micerevealed an anti-inflammatory effect of IFN-g in an RAmodel,collagen-induced arthritis (CIA). In the absence of IFN-gsignaling, the susceptible strain of mice (DBA/1) develops amore severe disease with rapid onset. Moreover, a resistantstrain of mice (C57BL/6) becomes susceptible when IFN-ggene is knocked out. The mechanism for breaking theresistance in IFN-g KO mice to CIA is not fully understood.Recently, interleukin-17 (IL-17) has been demonstrated toplay a critical role in development of CIA and has beenimplicated in the pathogenesis of RA. We hypothesized that

Abstracts S61