Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats

Table 2 Pathway analysis using Tian's method identified ERα agonist-regulated pathways related to immunity/inflammation.

rank	pathway	set size	percent up	average (NTk, NEk)
1	graft-versus-host disease	67	9	7.2
2	autoimmune thyroid disease	73	8	7.5
3	allograft rejection	68	9	7.8
4	cell adhesion molecules	189	18	8.0
5	retinol metabolism	64	11	9.5
6	type I diabetes mellitus	77	16	11.2
7	hematopoietic cell lineage	101	18	13.5
8	neuroactive ligand-receptor interaction	335	16	13.8
9	pantothenate and CoA biosynthesis	11	27	14.5
10	C and coagulation cascades	92	13	14.5
11	androgen and estrogen metabolism	33	15	16.5
12	Parkinson's disease	139	69	16.5
13	cytokine-cytokine receptor interaction	210	23	20.5
14	systemic lupus erythematosus	92	22	22.2
15	caffeine metabolism	10	10	25.5
16	metabolism of xenobiotics by cytochrome P450	48	15	26.2
17	ECM-receptor interaction	101	24	26.2
18	Jak-STAT signaling pathway	172	28	27.2
19	drug metabolism - other enzymes	38	24	27.5
20	basal cell carcinoma	68	21	29.0

The analysis identified eight immune-related KEGG pathways (in bold) regulated by selective ERα agonist 16α-LE2. In the analysis, KEGG pathways were used as collaborator gene sets. Using the Tian's method [31], the relationship between gene sets and treatment is quantified by two statistics (T _k and E _k) formulating the two hypotheses: i) the gene in a gene set shows the same pattern of associations with the treatment compared with the rest of the genes, ii) the gene set does not contain any genes whose expression levels are associated with the treatment, respectively. KEGG pathways were ranked by the mean of normalized statistics (NT _k and NE _k). Set size is the number of genes, percent up is the number of up-regulated genes in the KEGG pathway. C, complement.

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