The Role of PIKfyve in Toll-Like Receptor-Mediated Responses

Diseases

Number of patients

Results

Effect of apilimod on cytokine production

Ref.

Crohn’s disease

Significant

Burakoff et al. (2006)

Crohn’s disease

Significant

Billich (2007)

Crohn’s disease

220

Not significant

Sands et al. (2010)

Rheumatoid Arthritis

A small but significant

IL-12/IL-23p40→ (synovial CD68+ cell)

Krausz et al. (2012)

Psoriasis

Significant

IL-12/IL-23p40↓, IL-10↑ (skin lesions CD11c+ cells)

Wada et al. (2012)

Mouse (in vivo)

Mouse model (experimental autoimmune uveoretinitis)

Significant

IL-12↓ (serum)

Keino et al. (2008)

Mouse inflammatory bowel disease model

Significant

IFN-γ↓ (lamina propia mononuclear cells)

Wada et al. (2007)

IL interleukin, IFN interferon

The therapeutic effect of apilimod was also tested in a mouse model (experimental autoimmune uveoretinitis) by oral administration. The researchers who studied this mouse model reported a decreased level of serum IL-12p40 and a suppression of inflammation (Keino et al. 2008). Additionally, in vivo studies using a mouse inflammatory bowel disease model demonstrated that the oral administration of apilimod markedly reduced the inflammatory histological changes in the colon (Wada et al. 2007).

4.2.2 Apilimod, an Interleukin-12 Inhibitor, Is a PIKfyve Inhibitor

In 2007, apilimod was discovered by a biological strategy independent of the clinical tests. Wada et al. discovered this drug among an 80,000-compound library in a cell-based screen aimed at identifying an inhibitor of IL-12 production using interferon (IFN)-γ/lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs) (Wada et al. 2007). The IL-12 production induced by IFN-γ/Staphylococcus aureus Cowan I (SAC) was also susceptible to apilimod in PBMCs (Wada et al. 2007). The cytokine inhibitory spectrum of apilimod that was described by the paper published by Wada et al. is seen in Table 4.2.

Table 4.2

Cytokine inhibitory spectrum of PIKfyve inhibitors

Cell	Stimuli	Cytokine	Apilimod	TLR	Ref
Cell	Stimuli	Cytokine	IC₅₀ (nM)	TLR	Ref
Human PBMC	IFN-γ/SAC	IL-12p70	1	2	Wada et al. (2007)
Human PBMC	SAC	IL-12p70	5	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-23	10	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-12/IL-23p40	20	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IFN-γ	20	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-6	100	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-10	200	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	TNF-α	1,000	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-1β	>1,000	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-8	>1,000	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-18	>1,000	2	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-12p70	10	4	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-6	>1,000	4	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-10	>1,000	4	Wada et al. (2007)
Human PBMC	IFN-γ/SAC	IL-12p40	2.4	4	Cai et al. (2013)
Human PBMC	R837	IL-12p40	3	7	Cai et al. (2013)
Human PBMC	ssRNA	IL-12p40	2.8	7	Cai et al. (2013)
Human PBMC	ConA	IL-5	100		Wada et al. (2007)
Human PBMC	ConA	IL-4	20		Wada et al. (2007)
Human PBMC	αCD3/αCD28Ab	IFN-γ	400		Wada et al. (2007)
Human PBMC	αCD3/αCD29Ab	IL-4	40		Wada et al. (2007)
Human PBMC	αCD3/αCD30Ab	IL-2	800		Wada et al. (2007)
Human THP-1	IFN-γ/SAC	IL-12p70	10	2	Wada et al. (2007)
Human THP-1	IFN-γ/SAC	IL-6	>1,000	2	Wada et al. (2007)
Human THP-1	IFN-γ/LPS	IL-12p40	23	4	Cai et al. (2013)
Human THP-1	R848	IL-12p40	31	8	Cai et al. (2013)
Human THP-1	IFN-γ/LPS	IL-8	>1,000	4	Cai et al. (2013)
Human dendritic cells	IFN-γ/SAC	IL-12p70	1	2	Wada et al. (2007)
Human monocytes	IFN-γ/SAC	IL-12p70	5	2	Wada et al. (2007)
Mouse spleen cells	IFN-γ/SAC	IL-12p70	2	2	Wada et al. (2007)
Mouse PBMC	IFN-γ/SAC	IL-12p70	20	2	Wada et al. (2007)
Cell	Stimuli	Cytokine	Apilimod	TLR	Ref
Mouse BMDC	IFN-γ/LPS	IL-12p40	↓	4	Cai et al. (2013)
Mouse BMDC	IFN-γ/LPS	CXCL2	→	4	Cai et al. (2013)
Mouse BMDC	R848	IL-12p40	↓	7	Cai et al. (2013)
Mouse BMDC	R848	CXCL2	→	7	Cai et al. (2013)
Cell	Stimuli	Cytokine	YM201636	TLR	Ref
MEF	LPS	IFN-β (mRNA)	↓	4	Kawasaki et al. (2013)
MEF	polyI:C	IFN-β (mRNA)	↓	3	Kawasaki et al. (2013)
HEK293	LPS	ISRE (reporter assay)	↓	4	Kawasaki et al. (2013)
HEK293	polyI:C	ISRE (reporter assay)	↓	3	Kawasaki et al. (2013)
HEK293	LPS	NF-κB (reporter assay)	→	4	Kawasaki et al. (2013)
HEK293	polyI:C	NF-κB (reporter assay)	→	3	Kawasaki et al. (2013)
Mouse macrophage	CpG	IL-12p40	↓	9	Hazeki et al. (2013)
Mouse macrophage	CpG	IL-10	↓	9	Hazeki et al. (2013)
Mouse macrophage	CpG	TNF-α	↓	9	Hazeki et al. (2013)
Mouse macrophage	CpG	IL-1β	↓	9	Hazeki et al. (2013)
Mouse macrophage	LPS	IL-12p40	→	4	Hazeki et al. (2013)
Mouse macrophage	LPS	IL-10	↑	4	Hazeki et al. (2013)
Mouse macrophage	LPS	TNF-α	→	4	Hazeki et al. (2013)
Mouse macrophage	LPS	IL-1β	↓	4	Hazeki et al. (2013)

BMDC bone marrow-derived cell, CXCL C-X-C motif chemokine, HEK human embryonic kidney, IC ₅₀half-maximal inhibitory concentration, IFN interferon, IL interleukin, ISRE IFN-stimulated response element, LPS lipopolysaccharide, NF nuclear factor, PBMC peripheral blood mononuclear cell, SAC Staphylococcus aureus Cowan I, ssRNA single-stranded RNA, TLR Toll-like receptor, TNF tumor necrosis factor

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