Anti-inflammatory and immunomodulatory properties of Carica papaya

Figures & data

Table 1. In vivo studies of papaya extracts over immune-inflammatory markers.

Papaya
Parts	Extract	Route of administration - dose	Results	References
Leaf	Ethanol	Oral - 25–200 mg/kg	Significant (p < 0.05) reduction in carrageenan-induced paw edema, granuloma (cotton pellet induced) and inflammation in arthritic rats.	(Owoyele et al. 2008)
Leaf	Aqueous	Oral - 100–200 mg/kg	Leaf extract found to contain alkaloids, tannins, cardiac glycosides and saponins. Extract displayed significant (p < 0.05) anti-inflammatory effect in rats (using acetic acid-induced writhing response and formalin test).	(Adeolu and Vivian 2013)
Leaf	Juice	Oral - 0.2 ml, 7 d	Platelet count was enhanced after 21 d (5.53 × 10^5/μl to 11.3 × 10^5/μl) in mice. Increment in RBC count also observed (6 × 10^6/μl to 9 × 10^5/μl)	(Dharmarathna et al. 2013)
Leaf	Ethanol (70%)	Oral - 1.1g, twice daily, 12 d	Significant (p < 0.05) increment in platelet count was observed in dengue fever patients (male and female)	(Fenny et al. 2012)
Leaf	Juice	Oral - 150 ml, daily, 5 d	Increment in thrombocytes (28 × 10^3/μl to 138 × 10^3/μl) and WBC (3000/μl to 7800/μl) in male dengue fever patient	(Osama et al. 2014)
Leaf	Juice	Oral - 25 ml, twice daily, 5 d	Increment in platelets (55 × 10^3/μl to 168 × 10^3/μl), RBC (5.0 × 10^6/μl to 5.3 × 10^3/μl), WBC (3.7 × 10^3/μl to 7.7 × 10^3/μl) and PMN (46.7% to 78.3%) in male dengue fever patient	(Ahmad et al. 2011)
Leaf	Juice	Oral - 0.72 ml/100 g	Both mature and immature leaves displayed platelet enhancing property with no signs of toxicity and stress in rats	(Achini et al. 2012)
Leaf	Juice	Oral - 50 g, daily, 3 d	Mean platelet count enhanced in dengue fever patients at 40 h of first dose. ALOX12 (ΔCT mean = 16.02, FC = 15.00) and PTAFR genes (ΔCT mean = 14.87, FC =13.42) highly expressed	(Soobitha et al. 2013)
Fruit	–	Oral - 0.5 g/kg, daily, 3 weeks	Significant (p < 0.05) decrement in MPO and expression of iNOS in colitis-induced rat model	(Lima de Albuquerque et al. 2010)
Fruit	Aqueous	Oral - 0.25 g/kg, daily, 40 d	Significant (p < 0.05) decrement in MDA/SOD levels, increment in GSH/CAT levels in acrylamide (0.05%) toxicated rats (stomach, liver and kidney tissues)	(Mohamed Sadek 2012)
Fruit	–	Oral - 0.2 g and 1.6 g/kg for 5 weeks	No allergic potential displayed by transgenic and native papaya fruit on OVA-sensitized mouse model. Papaya green fruit (transgenic and non-transgenic) reduced IgM level (0.12–0.11 μg/ml vs. 0.15 μg/ml in control group)	(Chen et al. 2011)
Fruit	–	Oral - 100 g, thrice a day	Significant increments in CD4^+CD25^+CD127^- Treg cells (males) and level of IL-1β (male > female) were observed. Significant (p < 0.05) decrement in levels of IL-8, IL-6, IL-10, TNFα found in PBMC supernatants (in vitro study)	(Abdullah et al. 2011)
Fruit	Aqueous	Topical - 100 mg/kg, daily, 10 d	Significant (p < 0.001) increments in wound contraction capacity (77%) in diabetic rats and mass of granulation tissue were observed	(Nayak et al. 2007)
Seed	MeOH	Intraperitoneal - 50–200 mg/kg	Significant inhibition (57.1–64.2%) in inflammation observed in egg albumin-induced rat model	(Amazu et al. 2010)

MDA: malondialdehyde; SOD: superoxide dismutase; GSH: glutathione; CAT: catalase; OVA: ovalbumin.

Figure 1. Carica papaya-derived substances.

Table 2. Proteolytic enzymes and phytochemicals of C. papaya and their responses over inflammatory immune markers.

Substances; amount (papaya part)	Dose	Experimental systems	Anti-inflammatory and immunomodulatory activity	References
Proteolytic enzyme	30 μg/ml	PBMC	Significant (p < 0.05) increments in IL-6 and IFNγ	(Rose et al. 2006)
Papain; 53 000 ppm (unripe fruit latex), 2.43 mg/g (ripe fruit latex) (Rubens et al. 2000; Duke 2015)
					10 μg/ml	VEGF-activated human umbilical vein endothelial cells	Upregulation of ERK-1/2; downregulation of protein kinases AKT1, MEK1/2, p38-MAPK and SAPK/JNK.	(Mohr and Desser 2013)
	Alkaloids	1, 10 and 100 μg/ml	LPS stimulated PBMC	Significant (p < 0.001) decrements in the production of IL1β, IL10, TGFβ and TNFα	(Aldhous et al. 2008)
Nicotine; 102.8 ppm (leaf) (Duke 2015)
	0.1–100 μM					IL-18-enhanced PBMC	Inhibition of ICAM-1 expression, IFNγ production and proliferation of lymphocytes	(Takahashi et al. 2007)
	10 pM	LPS-activated monocytes	Significant decrements in TNFα, PGE2, MIP-1α, MIP-1α production and mRNA expression of TNFα, MIP-1α, COX-2. Suppression of IκB phosphorylation, subsequent inhibition NF-κB transcriptional activity	(Yoshikawa et al. 2006)
	0.1–100 μM	TNFα-induced fibroblast-like synoviocytes	Reductions in mRNA expression (IL-6 and IL-8) and NF-κB translocation.	(Zhou et al. 2012)
	2 mg/kg	Encephalomyelitis-induced female C57BL/6 mice, oral, for 28 d	Decrements of encephalitogenic Ag stimulated T-cell proliferation, production of TH1 (TNFα and IFNγ) and TH17 cytokines (IL-17, IL-17F, IL-21 and IL-22).	(Nizri et al. 2009)
	0.2 or 0.4 mg/kg	Male BALB/c mice, intra-peritoneal	Significant (p < 0.05) reductions in BALF cell numbers, MPO activity, pro-inflammatory chemokine (MIP-1α, MIP-2, eotaxin) and cytokine (IL-1, IL-6 and TNFα) levels.	(Mabley et al. 2011)
	1–2 mg/kg BW	Rat and mice, subcutaneous	Decrement in leukocyte migration, levels of chemokinesis, chemotaxis and chemokine-induced Ca^2+ responses in PBMC	(Razani-Boroujerdi et al. 2004)
	Choline 0.2 mg/g (leaf) (Ogan 1971)	1500 mg	Asthma patients, oral, twice daily	Significant (p < 0.01) reductions in IL-4, IL-5, TNFα, cysteinyl leukotriene and leukotriene B4 levels	(Mehta et al. 2010)
5 and 50 mg/kg BW		Mice (endotoxin induced), intraperitoneal	Reduction of serum TNFα	(Parrish et al. 2006)
Phenolics		50 mg/kg BW	Mice (ionizing radiation-induced inflammation), oral, 5 d	Prevention of increase in levels of inflammatory markers (COX-2 protein, iNOS-2 gene expression, lipid peroxidation, NF-κB translocation, TNFα and IL-6). Enhancement of SOD and CAT enzyme activities and reduction in GSH activity.	(Das et al. 2014)
Ferulic acid (FA) 1.87–2.78 mg/g (dry peel) (Gayosso-García Sancho et al. 2011)
	1.28 μg/gm BW					Mice (collagen-induced arthritis), IG, twice a day	Significant (p < 0.01) reduction of IL-1β and TNFα levels in serum and anti-inflammatory effects	(Zhu et al. 2014)
	p-Coumaric acid (PC); 0.33 mg/g (dry leaf), 1.36–2.23 mg/g (peel) (Canini et al. 2007; Gayosso-García Sancho et al. 2011)	2.4 μM	LPS-induced Caco-2 and RAW 264.7 co-culture	Reduction of levels of NO, IL-6, PGE-2, IL-1β, iNOS, COX-2, IκBα phosphorylation, TNFα mRNA	(Kim et al. 2014)
100 mg/kg BW		Mice (inflammation-induced), IP, 8 d	Significant (p < 0.05) reduction of synovial TNFα, delayed-hypersensitivity response and macrophage phagocytic function. Enhancement of serum IgG level and reduction of circulating immune complex.	(Pragasam et al. 2013)
Protocatechuic acid (PCA); 0.11 mg/g (dry leaf) (Canini et al. 2007)		2 mM	AGS	Significant (p < 0.05) decrement in migration of cells levels of MMP-2 and NF-κB protein.	(Lin et al. 2011)
	500 ppm	Rats (NMBA-induced esophageal cancer), SC	Decrements in expression of IL-1β, IL-2 and IL-10 (after 25 weeks).	(Peiffer et al. 2012)
	0.5–2%	Male Balb/cA mice, intraperitoneal, daily, 8 weeks	Significant (p < 0.05) decrements in levels of IL-1β, IL-6, TNFα, PGE2, NF-κB and COX-2 protein (vs D-galactose-fed mice).	(Tsai & Yin 2012)
	25–100 mg/kg	Rats (edematous/arthritic model), oral, 8 d (for anti-inflammatory) and 14 d (for anti-arthritic)	Displayed anti-inflammatory and anti-arthritic activity. Significant reduction of NO and lipid peroxides activity. In addition, increment in levels of anti-oxidant enzymes (such as GSH, CAT and SOD).	(Lende et al. 2011)
	Quercetin; 0.04 mg/g (dry leaf), 0.83–2.57 μg/g (fruit) (Canini et al. 2007; Kongkachuichai et al. 2010)	1 μM	PBMC and human, 4 weeks	Decrement in levels of cytokines (77%). Enhancement in total anti-oxidant levels	(Boots et al. 2008)
1–50 μM		Dendritic cells (DC isolated from C57BL/6 mice)	Inhibition of LPS-induced DC activation at 1 μM. Significant reductions in levels of various pro-inflam-matory cytokines (IL-1α, IL-1β, IL-6, IL-10, IL-12) and chemokines (MCP-1, MIP-1α, MIP-1β, RANTES). Suppression of endocytosis, DC migration and ability to induce Ag-specific T-cell activation	(Huang et al. 2010)
50 μΜ and 1 mg/kg		Rats (colitis-induced) and macrophages, oral treatment to rats for 14 d	Significant inhibition of TNFα, IL-1β, iNOS expression and NF-κB activation	(Comalada et al. 2005)
1–50 μM		PBMC	Reduction of TNFα and NF-κB gene expressions	(Madhavan et al. 2006)
Kaempherol; 0.03 mg/g (dry leaf), 0.004–0.006 μg/g (fruit) (Canini et al. 2007; Kongkachuichai et al. 2010)		40 mM	HL-60, U937, M12, and A1.1, PBMC, Primary BALB/c splenic cell	Decrements in activation of JAK3, STAT6 and mixed lymphocyte culture proliferation	(Cortes et al. 2007)
	1–10 μM	Aldosterone-induced primary HUVEC cells	Reductions in levels of ROS, OPN, CD44, phospho-p38MAPK expression and NF-κB	(Liu et al. 2014)
	10/20 mg/kg 1–20 μM	BALB/c mice (allergic asthma), oral for 3 d and BEAS-2B cells	Significant decrements in eotaxin-1 protein expression (LPS-induced), integrin β2, eosinophil adhesion (to TNFα-activated airway epithelium), MCP-1 transcrip-tion (TNFα-activated) and NF-κB. Reduced PMN and basophils count. Diminished IκB phosphorylation	(Gong et al. 2012)
	10–100 μM	BV2 (LPS-induced microglial cells)	Significant (p < 0.05) reductions in inflammatory markers (NO, PGE2, TNFα, IL-1β, iNOS, cox-2, MMP-3) and blocked activation of TLR4. Inhibition of NF-κB activation and phosphorylation (p38 MAPK, JNK and AKT)	(Park et al. 2011)
	150 and 30 mg/kg BW	Cholesterol-fed rabbits	Significant reductions in TNFα, IL-1β, MDA levels. Enhanced serum SOD activity	(Kong et al. 2013)
	Carotenoids	1.5 mg/kg	Rats (myocardial infarct), gastric gavage, daily, 28 d	Significant (p < 0.05) inhibition of macrophage infil-tration, TNFα expression, phosphorylation of IKKα/β and NF-κB activation	(Yongming & Wang 2014)
Lycopene; 1.5–12 μg/g (unripe flesh), 11.5 μg/g (ripe red flesh) (Yamamoto 1964; Rivera-Pastrana et al. 2010)
	0.5–2 μM					Cigarette smoke extract-induced THP-1 cells	Decrements in immune marker (IL-8 expression, ROS, NF-κB/p65 nuclear translocation) levels, phos-phorylation (IKKα and IkBα) and redox-sensitive kinases (ERK1/2, JNK and p38 MAPKs).	(Simone et al. 2011)
	0.5–2 μM	LPS-stimulated RAW 264.7, 3T3-L1	Significant inhibition of macrophage migration, TNF-α and mRNA (adiponectin, MMP-3, MMP-9) levels. Inhibition of JNK and NF-κB pathways.	(Marcotorchino et al. 2012)
	2 μM	C57BL/6j mice and 3T3-L1 pre-adipocytes	Decrements in levels of mRNA (IL-6, MCP-1, IL-1β, TNFα) and NF-κB (TNFα-activated).	(Gouranton et al. 2011)
	β-Cryptoxanthin; 3.1–8.0 μg/g (unripe flesh), 16.9 μg/g (ripe red flesh) (Yamamoto 1964; Rivera-Pastrana et al. 2010;)	7.5 and 37.5 μg/kg BW	Ferrets (cigarette smoke-induced), oral 3 mo	Significant decrements in TNFα levels (bronchial and alveolar epithelial cells), NF-κB expression (AP-1), 8-OHdG and macrophages (lung tissue). Reduction in metaplasia (lung squamous) and inflammation (lung).	(Liu et al. 2011)
5 and 10 mg/kg BW		Rabbit, oral, daily, 21 d	Enhancement in count of CD4^+ lymphocytes (p < 0.01) in rabbit blood. Significant (p < 0.05) enhancement in IL-4 and immunoglobulins (IgG, IgM, IgA).	(Ghodratizadeh et al. 2014)
0.003%		C56BL/6J mice (cholesterol diet-induced), oral, 12 weeks	Downregulation of fibrosis, fat accumulation, increases in Kupffer and activated stellate cells. Suppression of T-cell markers and inflammatory gene expression.	(Kobori et al. 2014)
β-Carotene; 2.3–3.1 μg/g (unripe flesh), 7.0 μg/g (ripe red flesh) (Yamamoto 1964; Rivera-Pastrana et al. 2010)		60 mg/kg	C57BL/6 mice, IP, 5 doses for 5 d; and B16F-10 melanoma cells	Significant downregulation in TNFα, IL-6, VEGF. Significant enhancement in IL-2 and metalloprotease. Significant (p < 0.001) reduction in pro-inflammatory cytokine production (B16F-10 cells). Inhibition of NF-κB subunit (p65, p50, c-Rel) translocation	(Guruvayoorappan & Kuttan 2007)
	5 mg/kg	Mice, orally, 7 d	Significant enhancement in IL-2 and IFNγ levels	(Yamaguchi et al. 2010)
	2 - 20 μM	AGS (Helicobacter pylori-induced)	Decrements in levels of markers (ROS, iNOS, COX-2) and transcription kinase (MAPK, p38, JNK, NF-κB, AP-1) activation	(Jang et al. 2009)
	Lutein; 7.1 μg/g (fruit) (Ben-Amotz & Fishler 1998)	0.1 g/100 g diet	Guinea pig, oral, 12 weeks	Significant (p < 0.05) reduction in inflammatory IFNγ, TNFα, IL-1β, IL-2, -4, -5, -6, -7, -10, -12 levels	(Kim et al. 2011)
1–20 mg		Cat and dog, oral, daily,12 weeks	Significant enhancement in lymphocytes (CD4^+, CD21^+). Nonsignificant effect on pan-T, CD8, MHC-II marker levels. Enhanced plasma IgG (p < 0.05; cats)	(Kim et al. 2000a, 2000b)
Glucosinolates		150 and 300 nM 1–5 μM	Mice, topical and Raw 264.7 cells (LPS stimulated)	Reduction in ear edema. Decreased immune markers (NO production, iNOS protein/mRNA, PGE2, COX-2 protein, NF-κB signaling) and IL-6, IL-1β, TNFα	(Lee et al. 2009)
Benzylisothiocynate; 4.6 μmole/g seed, <0.003 μmole/g pulp, 141.7–342.7 ppm seed, 23.3–45.1 ppm pericarp, 21.2–43.1 ppm pulp, 2910 ppm (ripe fruit seed), 4 ppm ripe fruit pulp, 52.2 mg/kg leaf, 18 mg/kg unripe fruit, 3.6 mg/kg flower (Tang 1971; Sheu & Shyu 1996; Nakamura et al. 2007; Li et al. 2012)
	810 nmol					Mice (TPA-induced oxidative damage), topical and HL-60 cells	Significant (p < 0.05) inhibition of MPO activity and O^2- generation. Enhanced TUNEL^+ index in mouse skin.	(Miyoshi et al. 2004)

A1.1: murine lymphocyte; AGS: human gastric carcinoma cells; AKT: protein kinase B; BALF: bronchoalveolar lavage fluid; BEAS-2B: Human airway epithelial; CaCo-2: Colon cancer cell; CAT: catalase; Cox-2: cyclooxygenase-2; DC: dendritic cells; ERK: extracellular signal-regulated kinases; GSH: glutathione; HL-60: human promyelocytic leukemia cells; HUVEC: human umbilical vein endothelial cells; JNK: c-Jun N-terminal kinases; M12: human prostate cell line; MAPK: mitogen-activated protein kinase; MEK-1: mitogen-activated protein kinase kinase 1; MHC: major histocompatibility complex; MIP-2: macrophage inflammatory protein-2; MMP-2: matrix metalloproteinase; NK: natural killer cell; NMBA: N-nitrosomethylbenzylamine; NLRP-3: OPN: osteopontin; PGE-2: prostaglandin E2; RAW 264.7: murine macrophages; ROS: reactive oxygen species; SOD: superoxide dismutase; TGF-β: Transforming growth factor beta; THP-1: human acute monocyte leukemia cell; TLR-4: Toll-like receptor 4; TPA: 12-O-tetradecanoylphorbol-13-acetate; TUNEL: terminal deoxynucleotidyl transferase-dUTP nick end labeling; U937: human leukemic monocyte lymphoma cell line; VEGF: vascular endothelial growth factor; 8-OHdG: 8-Oxo-2'-deoxyguanosine.

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