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Am J Neurodegener Dis 2012;1(3):305-315

Original Article
Tocilizumab attenuates inflammation in ALS patients through inhibition of
IL6 receptor signaling

Mathew T Mizwicki, Milan Fiala, Larry Magpantay, Najib Aziz, James Sayre, Guanghao Liu, Avi Siani, Derrick Chan,
Otoniel Martinez-Maza, Madhuri Chattopadhyay, Antonio La Cava

Department of Surgery, David Geffen School of Medicine at UCLA, 650 Charles E. Young Dr. South, Los Angeles, CA
90095-1735, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 650
Charles E. Young Dr. South, Los Angeles, CA 90095-1735, USA; Department of Pathology and Laboratory Medicine,
David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095-1732, USA; Department of
Biostatistics, University of California School of Public Health, Los Angeles, CA; Department of Chemistry and
Biochemistry, UCLA, Los Angeles, CA; Department of Medicine, David Geffen School of Medicine at UCLA, 650 Charles
E. Young Dr. South, Los Angeles, CA 90095-1735, USA;

Received October 22, 2012; accepted November 18, 2012; Epub November 21, 2012; published November 30, 2012

Abstract: Patients with amyotrophic lateral sclerosis (ALS) have evidence of chronic inflammation demonstrated by
infiltration of the gray matter by inflammatory macrophages, IL17A-positive T cells, and mast cells. Increased serum
levels of IL6 and IL17A have been detected in sporadic ALS (sALS) patients when compared to healthy controls.
Herein we investigate, in peripheral blood mononuclear cells (PBMCs), the baseline transcription of genes associated
with inflammation in sALS and control subjects and the impact of the IL6 receptor (IL6R) antibody (tocilizumab) on
the transcription and/or secretion of inflammation factors (e.g. cytokines) stimulated by the apo-G37R superoxide
dismutase (SOD1) mutant. At baseline, PBMCs of four sALS patients (Group 1) showed significantly increased
expression of TLR2 and CD14; ALOX5, PTGS2 and MMP1; IL1α, IL1β, IL6, IL36G, IL8 and TNF; CCL3, CCL20, CXCL2,
CXCL3 and CXCL5. In four other sALS patients (Group 2), most of the genes just mentioned were expressed at near
control levels and a significant decrease in the expression of PPARG, PPARA, RARG, HDAC4 and KAT2B; IL6R, IL6ST
and ADAM17; TNFRSF11A; MGAT2 and MGAT3; PLCG1; CXCL3 were detected. Apo-G37R SOD1 up regulated the
transcription of cytokines (e.g. IL1α/β, IL6, IL8, IL36G), chemokines (e.g. CCL20; CXCL3, CXCL5), and enzymes (e.g.
PTGS2 and MMP1). In vitro, tocilizumab down regulated the transcription of many inflammatory cytokines, chemokines,
enzymes, and receptors, which were up regulated by pathogenic forms of SOD1. Tocilizumab also reduced the
secretion of the pro-inflammatory cytokines IL1β, IL6, TNFα, GM-CSF, IFNγ, and IL17A by Group 1 PBMCs. Finally,
sALS patients had significantly higher concentrations of IL6, sIL6R and C-reactive protein in the cerebrospinal fluid
when compared to AD patients. This pilot study demonstrates that in vitro tocilizumab suppresses many factors that
drive inflammation in sALS patients, with possible increased efficacy in Group 1 ALS patients. (AJND1210006).

Keywords: Tocilizumab, amyotrophic lateral sclerosis (ALS), chronic inflammation, IL6 receptor signaling

Address all correspondence to:
Dr. Milan Fiala
100 UCLA Medical Plaza, Suite 220
Los Angeles, CA 90095, USA.
E-mail: Fiala@mednet.ucla.edu