Potassium and malaria

Potassium, the most abundant cation in the human body, regulates intracellular enzyme function and neuromuscular tissue excitability. Serum potassium is normally maintained within the narrow range of 3.5 to 5.5 mEq/L. During malaria infection the cytoplasm of infected erythrocytes is poor in potassium and rich in sodium, a drastic change compared to non infected erythrocytes. H. Ginsburg,S. Handeli, S. Friedman. Effects of red blood cell potassium and hypertonicity on the growth ofPlasmodium falciparum in culture. Zeitschrift für Parasitenkunde, March 1986, Volume 72, Issue 2, pp 185–199 pH also plays a key role: it is 7.20 in the cytoplasm and 5.10 in the food vacuole. The parasite plasma membrane potential changes with extracellular potassium concentration : it depolarizes at higher concentrations and hyperpolarizes a low concentrations. R Allen, K KirkThe Membrane Potential of the Intraerythrocytic Malaria Parasite Plasmodium falciparum. Journal of Biological Chemistry 279(12):11264-72 · April 2004. DOI: 10.1074/jbc.M311110200 , Hypokalemia (plasma potassium concentrations below normal range) has been recognized over recent years to be very frequent in malaria and not only in severe malaria. In a study of 1415 patients in Thailand 44% of the patients infected by Plasmodium falciparum and Plasmodium vivax were hypokalemic. Vipa Thanachartwet, Srivicha Krudsood, Hyponatraemia and hypokalaemia in adults with uncomplicated malaria in Thailand , Trop Doct July 2008 38: 155-157, doi:10.1258/td.2007.070112 Similar percentages were found in India and in Nigeria J. Ikekpeazu Ebele, E. Neboh Emeka , C. Aguchime Nnenna , C. Maduka Ignatius and A. Aronu EbeleMalaria Parasitaemia: Effect on Serum Sodium and Potassium Levels International. Journal of Tropical Medicine2010 | Vol 5 | Issue: 2 | 46-49 and in Kenya. Potassium deperdition is enhanced by vomiting, sweating and diarrhoea. Urinary potassium wasting is high. Maitland K, Pamba A , Newton CR , Lowe B , Levin M 2004, 5(1):81-85Hypokalemia in children with severe falciparum malaria. DOI: 10.1097/01.PCC.0000102398.91277.08. S Rathod, Study of sodium and potassium ion disturbances in malaria at Ahmeddabad. Internat Arch Integrat Medic. 2014 1.1. 7-11. Hypokalemia is more pronounced for Plasmodium falciparum than for Plasmodium vivax. This might explain the higheer morbidity and mortality for falciparum malaria. JH Jasani, S Sancheti, K Bhuva, L Dhairya. Association of the electrolyte disturbances with the type and severity of the malarial parasite infection. J Clinic and Diagnostic Res, 2012, 6, 678-681 From the existing literature, it is clear that hypokalemia is now a well documented phenomena in malaria patients and may have been highly underestimated. It also has been noticed in chikungunya and in dengue often leading to hypokalemic paralysis Jha S, Ansari M K. Dengue infection causing acute hypokalemic quadriparesis. Neurol India, 2010 58, 592-594 Sagar Sinha Ananya Mukherji and Santwana Chandrakar. Hypokalaemic paralysis in an adult case of Plasmodium vivax malaria. Malaria Journal201312:111 DOI: 10.1186/1475-2875-12-111 Hypokalemia may reach life-threatening levels and cause paralysia. The paatient could be cured by intravenous potassium chloride injection. The authors recommend that in endemic areas physicians must monitor potasssium levels in cases presenting similar symptoms. Sagar Sinha, S Mukherij, S Chandrakar. Hypokalaeemic parlysis in an adult case of Plasmodium vivax Malaria. Malaria J, 2013, 12.111. Arginine is known to improve endothelial function in malaria and it raises potasssium levels. A 12 gr injection of arginine raises the plasma potassium level from 3.3 mmol/L to 3.7. T W Yeo, DA Lampah, R Gitawati, N Anstey. Safety profile of L-arginine infusion in moderately severe falciparum malaria. PLoS ONE, 2008. 3. 6, e2347 Potassium enhanes NO release. A large body of evidence supports the view of a strong relation between sodium intake and the development of hypertension. In contrast potassium intake has been shown to have a beneficial effect on the cardiovascular system. Increased potassium swells endothelial cells and modifies endothelial cell stiffness. Artemisia plants are very rich in potassium and contain virtually no sodium. H. Oberleithner, C Callies, HE de Wardener. Potassium softens vascular endothelium and increases nitric oxide release, PNAS, 2009, 106,8, 2829-2834 The voltage gated potassium channel plays an important role in parasite survival. In a medium with high potassium concentration the invasion of erythrocytes by merozoites is inhibited W Trager and J Williams. Extracellular (axenic) development in vitro of the erythrocytic cycle of Plasmodium falciparum. Proc Natl Acad Sci U S A. 1992 Jun 15; 89(12): 5351–5355. Low potassium concentrations provide the signal that triggers proteins at the merozoite apicoplast which find receptors at the erythrocyte surface leading to the subsequent invasion Subhash Singh, Matthew Plassmeyer, Deepak Gaur, and Louis H. Miller Mononeme: A new secretory organelle in Plasmodium falciparum merozoites identified by localization of rhomboid-1 proteaseProc Natl Acad Sci U S A. 2007 Dec 11; 104(50): 20043–20048. doi: 10.1073/pnas.0709999104 The ineffectiveness of Azadirachta indica (neem) as antimalarial may be related to the high concentration of sodium in this plant 500 to 1000 times higher than potassium. A situation which is just the opposite for Artemisia annua. TS Djenontin, V Wotto, F Avelessi, D Pioch. Composition of Azaridachta indica and Carapa procera seed oils. Industrial crops and products Chloroquine therapy leads to an increase of potassium in the infected red blood cells M. J. DunnAlterations of Red Blood Cell SodiumTransport during Malarial Infection M Dunn, J Clinic Investigat, 1969, 48, 674-682 Dietary potassium also reduces hypertension and acts as antioxidant by reducing ROS production. Ando K, Matsui H, Fujita M, Fujita T. Protective effect of dietary potassium against cardiovascular damage in salt-sensitive hypertension: possible role of its antioxidant action. Curr Vasc Pharmacol. 2010 Jan;8(1):59-63. More disturbing is the fact that artemisinin and its derivatives can potentially cause hypokalemia. They have been known to affect voltage-gated potassium currents, and their administration in patients of hypokalemia has been known to prolong the QT-interval. Hara Y, Yamawaki H, Shimada M, Okada K, Tanai T, Ichikawa D, Miyake K, Kizaki K. Anticholinergic effects of artemisinin, an antimalarial drug, in isolated guinea pig heart preparations. J Vet Med Sci. 2007 Jul;69(7):697-702. Artemether significantly increases the potassium concentration in urine R.O. Akomolafe, I.O. Adeoshun, J.B. Fakunle, Effects of artemether on the plasma and urine concentrations of some electrolytes in rats Afric J of Biotechnology, 2011, 10 (20), 4226-4233. DOI: 10.5897/AJB07.500 The same diuretic effect has been noticed for artesunate Syed Ahmed Zaki, Preeti Shanbag, Vijay Lad, and Prithi Shenoy Sodium artesunate-induced diuresis in a patient with malaria Indian J Pharmacol. 2011 Jul-Aug; 43(4): 472–473. doi: 10.4103/0253-7613.83129 In fact the severe diuretic effect of intravenous injection of artesunate is known since 2002 Seguro AC, Campos SBDiuretic effect of sodium artesunate in patients with malaria. Am J Trop Med Hyg. 2002 Nov;67(5):473-4. The use of artesunate recommended by WHO for intravenous injections is thus a double-edged weapon : the increased urinary loss of water and electrolytes can worsen renal failure. Low plasma potassium can of course be modified by oral or intravenous injection. But there appears to be another treatment which merits more research. Among all the medicinal plants those of the Artemisia family have the highest potassium content. The first to report this wasa USDA team E Brisibe, E. Umoren , Pedro M. Magalhäes ,Jorge F.S. Ferreira. Nutritional characterisation and antioxidant capacity of different tissuesof Artemisia annua L. Food Chemistry, 2008, 115, 1240-46 Many medicinal plants, for example cherry stems (Prunus avium) are rich in potassium. Potassium concentrations in Artemisia annua are 10 to 100 times higher than those of other minerals, particularly sodium. A study in Morocco measured the potassium content of four medicinal plants. For Artemisia herba alba it is the highest B. Imelouane, M. Tahri , M. Elbastrioui, F. Aouinti, A. Elbachiri. Mineral Contents of Some Medicinal and Aromatic Plants Growing in Eastern Morocco J. Mater. Environ. Sci. 2 (2) (2011) 104-111 Imelouane et al.104 A more complete study in Pakistan, comparing 10 medicinal plants finds that potassium content in Artemisia annua is the highest Iqbal Hussain. Evaluation of Inorganic Profile of Selected Medicinal Plants of Khyber Pakhtunkhwa Pakistan. World Applied Sciences Journal 12 (9): 1464-1468, 2011 ISSN 1818-4952 A Tunesian study finds higher concentrations of potassium in Artemisia herba alba and A campestris than in Rosmarinus or Thymus. An extensive study at the University of Islamabad analyzed the elemental content in 17 indigenous species of Artemisia that are commonly used against ailments in Pakistan. (A. scoparia, A. absinthium, A. indica, A. santolinifolia, A. maritima, A. vulgaris, A. japonica, A. nilagirica, A. herba-alba, A. annua, A. brevifolia, A. moorcroftiana, A. dracunculus, A. roxburghiana and A. dubia). In all potassium concentrations are high in a fairly narrow range around 16 000 ppm and most of them are known to have antimalarial properties M Ashraf, MQ Hayat, S Jabeen, N Shaheen, MA Khan, G Yasmin Artemisia L. species recognized by the local community of northern areas of Pakistan as folk therapeutic plants, J Med Plants Res 4, 112-119 In 1982 already the University of Wyoming conducted a study on minerals in Artemisia filigrana. Again potassium was very high and much more in the young plants. Rauzi, F., 1982. Seasonal Variations in Protein and Mineral Content of Fringed Sage Worth (Artemisia frigida), J. Range Management, 35(5): 679-680. In our own research work with the University of Dakar Traore Alassane, Diallo Mouhamadou, Gueye Papa El Hadji Omar, Wague Ahmadou, Lutgen Pierre. Characterization of element and mineral content in Artemisia annua and Camellia sinensis leaves by handheld X-ray fluorescence . African Journal of Biotechnology Vol. 12(26), pp. 4179-4186, 26 June, 2013 Luz Estella Mesa, Pierre Lutgen, Ivan D. Velez, Angela M. Segura and Sara M. Robledo. Artemisia annua L., Potential Source of Molecules with Pharmacological Activity in Human Diseases AJPCT[3][05][2015] 436-450 we had found that the concentrations of potassium in Artemisia annua from different origins was twice as high as in Camelia sinensis.. Avocados are vey rich in potassium too. Plasmodium needs to import choline to produce phospholipids, probably in order to limit the diffusion of ROS into the erythrocyte. The high concentration of potassium in Artemisia plants may have an important role. The ability of human erythrocytes to accumulate choline is abolished when external Na is replaced by K and the efflux of choline is increased. K Martin, Extracellular cations and the movement of choline across the erytrocyte membrane. J Physiol, 1972, 224, 207-230. The choline uptake is influenced by the electronegativity of the plasma membrane. When the concentration of potassium ions is increased, the membrane becomes depolarized. The choline absorption decreases majorly as a result of the membrane depolarization by the potassium ions. The choline uptake was found to be only affected by the potassium ions. The sodium ions do not affect this uptake. Beniko Iwaoa, Miki Yarab, Naomi Harab, Yuiko Kawaic, Neurochemistry International. Volume 93, February 2016, Pages 40–50. Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells Many research efforts on Artemisia probably have missed this point because they work with extracts obtained in organic solvents. Only aqueous infusions and powdered leaves in capsules or tablets will deliver this essential constituant to malaria patients. The well known therapeuticac efficacy of all genotypes from the large Artemisia family against many diseases might to a large extent be related to their high concentration in potassium. The antioxidant efficiency of Artemisia annua has been described in several papers. Artemisia afra even has stronger antioxidant properties (VUB, unpublished data). The mechanism of this action is not well understood and very complex. Potassium is known for its antioxidant properties Hiromitsu Matsui, Tatsuo Shimosawa, Yuzaburo Uetake Protective Effect of Potassium Against the Hypertensive, Cardiac Dysfunction Hypertension. 2006; 48:225-231.) Association With Reactive Oxygen Species Reduction Ando K, Matsui H, Fujita M, Fujita TProtective effect of dietary potassium against cardiovascular damage in salt-sensitive hypertension: possible role of its antioxidant action. Curr Vasc Pharmacol. 2010 Jan; 8(1):59-63. As the concentration of potassium in Artemisia herb is exceptionnally high, could this to some extent explain the antioxidant properties and health benefits related to this. On invading an uninfected human erythrocyte Plasmodium falciparum enters a low sodium, high potassium environment. It establishes new permeability pathways which allow the influx of sodium and efflux of potassium until reaching levels approaching those in the extraerythrocytic plasma., or eventually higher, leading to swelling and explosion of the erythrocyte. This flow is accelerated in late stages of schizont developpement. Duke JA (2001) Handbook of phytochemical constituents of GRAS herbs and other economic plants. CRC Press LLC, Boca Raton, FL p 70 Dunn MJ Alterations in red blood cell sodium transport during malarial infection. J Clin Invest (1969) 48:674-684 Karena L Waller, Sean M McBride, Kami Kim. Characterization of two putative potassium channels in Plasmodium falciparum. Malaria Journal20087:19DOI: 10.1186/1475-2875-7-19 These new pathways allow Na+ influx, causing [Na+] in the infected erythrocyte cytosol to increase to high levels. The intraerythrocytic parasite itself maintains a low cytosolic [Na+] via unknown mechanisms and extrudes Na+ against an inward gradient via PfATP4, a specific parasite plasma membrane protein. This pfATP4 pump plays a critical role for plasmodium and other apicoplasts. During the asexual life cycle of Plasmodium falciparum it shows a 5-fold increase from the ring stage to the merozoit stage Krishna S, Woodrow C, Webb R, Penny J, Takeyasu K, Kimura M, East JM.Expression and functional characterization of a Plasmodium falciparum Ca2+-ATPase (PfATP4) belonging to a subclass unique to apicomplexan organisms. J Biol Chem. 2001 Apr 6;276(14):10782-7. Epub 2001 Jan 5. It needs to be reminded that potassium and sodium always interact in the whole body and its parts. That means for example that increased potassium will drive sodium out. Some chemical molecules like pyrazoleamides or spiroindolones have been described recently in the literature to cause a rapid disruption of sodium regulation in blood stage Plasmodium faciparum parasites Akhil B. Vaidya, Lawrence W. BergmanPyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum. Nature Communications 5, Article number: 5521 (2014)doi:10.1038/ncomms6521 Cytoplasmic calcium is essential for malaria parasite egress from infected erythrocytes. A steady increase is found to preceed this egress Svetlana Glushakova, Vladimir Lizunov, Paul S Blank, Cytoplasmic free Ca2+ is essential for multiple steps in malaria parasite egress from infected erythrocytes. Malaria Journal 201312:41 DOI: 10.1186/1475-2875-12-41 In Toxoplasma gondii it has been observed that the reduction in the host cell potassium causes an increase in cytoplasmic calcium. As long as the host cells are healthy enough to maintain their normal cytosolic ion composition, they provide a suitable environment for parasite growth and the parasite will remain in the cell. If the resources of the host cell become exhausted due to the metabolic burden, a decrease in cytoplasmic potassium is noticed and this signal triggers the egress because the host cell can no longer support the replication and survival of the parasite Moudy R, Manning TJ, The loss of cytoplasmic potassium upon host cell breakdown triggers egress of Toxoplasma gondii. J Biol Chem. 2001 Nov 2;276(44):41492-501. Epub 2001 Aug 28. A more recent in vitro study confirms most of these findings Pillai AD, Addo R, Sharma P, Nguitragool W, Srinivasan P, Desai SAMalaria parasites tolerate a broad range of ionic environments and do not require host cation remodelling. Mol Microbiol. 2013 Apr;88(1):20-34. doi: 10.1111/mmi.12159. The standard medium used for Plasmodium falciparum culture is human serum. It fulfills the requirement that the extracellular sodium concentration be high because the entry of sodium into infected cells is passive. When sodium is replaced by lithium or potasssium the parasite growth is interrupted. This may reflect on an indirect toxic effect of high potassium concentrations. This indirect toxicity might be related to the fact that potassium has a higher PSAC (plasmodium surface anion channel) permeability than sodium leading to osmotic lysis of infected cells. Potassium enrichment of the plasma leads to osmotical shrinkage of the infected erythrocyte, increased viscosity in the host cell cytoplasm and hemoglobin gelation. The supply of potassium acts like an antimalarial. The authors of this research work demonstrated that potassium really was an inhibitor of parasite growth, by adding sucrose to the parasite cultures. Sucrose acts as an impermeant of the PSAC channels and blocks the entry of extracellular potassium into the cytosol. The precise contribution of potassium in plasmodium merozoite maturation and invasion should be reevaluated in light of these studies. The potassium channels in apicomplexan parasites like Plasmodium, Toxoplasma, Paramecium become novel targets for anti-parasitic drugs. Many molecules present in Artemisia plants have an effect on erythrocyte cell membrane structure, permeability and cationic channels : phytosterols Hac-Wydro K1. The replacement of cholesterol by phytosterols and the increase of total sterol content in model erythrocyte membranes. Chem Phys Lipids. 2010 Sep;163(7):689-97. doi: 10.1016/j.chemphyslip.2010.07.001. steroids, Mary Luz López, Silvia Blair, Jairo Sáez, Cesar Segura. Effect of Solanum nudum steroids on uninfected and Plasmodiumfalciparum-infected erythrocytes Mem Inst Oswaldo Cruz, Vol. 104(5): 683-688, August 2009 scopoletin. Oliveira EJ1, Romero MA, Silva MS, Silva BA, Medeiros IA. Intracellular calcium mobilization as a target for the spasmolytic action of scopoletin. Planta Med. 2001 Oct;67(7):605-8. Scopoletin is a key constituent of many Artemisia species and probably contributes to their antimalarial efficiency in vivo. Scopoletin is a coumarin ; their action is known as ionic channel opener and blocker. US Patent 8,067,619 B2 2006 claims their effect on potassium channel potential and their beneficial effect on a number of diseases : overactive bladder, benign prostate hyperplasia, stroke, pain, ischemia…. Scopoletin is absorbed by erythrocytes in which it binds to the haemoglobin and affects erythrocyte structure and oxygen capture and delivery. Gloria Daniel-Igwe. Hepatic Necrosis and Degenerative Myopathy Associated with Cassava Feeding in Pigs. Journal of Veterinary Medicine. Volume 2014 (2014), Article ID 584945,.doi.org/10.1155/2014/584945 Could potassium explain the mystery of malaria immunity in babies ? Although 80% of malaria occurs in children under five years of age, infants under six months of age are known to have low rates of infection and disease. It is not clear why this youngest age group is protected. The perception that malaria is uncommon in young infants has resulted in the paucity of information currently available and the lack of evidence-based treatment guidelines in this population. Many children are dying before malaria is diagnosed and the death toll for infants under aged under six months is estimated at 200 000 – 300 000 annual casualties. The general belief was that foetal blood cells predominant in the newborn were relatively resistant to penetration by the malaria parasite. A recent paper however shows that in an in vitro culture using fœtal erythrocytes from malaria infected mothers comparable growth rates are found for those with maternal red blood cells and those from non-malaria exposed individuals. But cultures in foetal plasma showed both significantly lower growth rates than a positive control using non-malaria exposed donor plasma. These data challenge the concept that fœtal hemoglobin is an intrinsic inhibitor of Plasmodium falciparum growth in the first months of life. However addition of cord plasma led to reduced in vitro growth Sauerzopf U, Honkpehedji YJ, Adgenika AA, Feugap EN, Ngoma GM, Mackanga JR, Lötsch F, Loembe MM, Kremsner PG, Mordmüller B, Ramharter M , In vitro growth of Plasmodium falciparum in neonatal blood. Malar J. 2014 Nov 18;13:436. doi: 10.1186/1475-2875-13-436. Similar experiments had been run already in 1984. Erythrocytes in standard culture medium showed a heavy invasion with young rings of previously uninfected red cells. In a medium of high potassium content this invasion was inhibited and many free merozoites were present. W Trager and J Williams. Extracellular(axenic) development in vitro of the erytrocytic cycle od Plasmodium falciparum. Proc Natl Sc USA. 1992 jun 15; 89 (12) 53521-55 It is likely that potassium plays a key role. The potassium concentration in the plasma of neonates is much higher than in the plasma of the mothers: 5.9 mmol/l versus 3.8 mmol/l Martinerie L, Pussard E, Foix-L'Hélias L, Petit F, Cosson C, Boileau P, Lombès M. Physiological partial aldosterone resistance in human newborns. Pediatr Res. 2009 Sep;66(3):323-8. Potassium concentrations in mother’s milk are 2 times higher at postpartum in colostrum than 1 month later in mature milk. Silprasert A, Leelapat PPruenglampoo, Composition of sodium, potassium, calcium, magnesium and phosphorus in human g breat-milk at different stages of lactation period, 1991. Http://thaiagris.lib.ku.ac.th It appears that everything is done to protect the fœtus and the neonate against hypokalemia. The fœtal homeostatis for potassium appears to be very efficient. In maternal rats fed a diet deficient in potassium during pregnancy the plasma level of K fell to one-half the normal value. The K concentration in fœtal plasma did not change significantly. However in the case of depleted sodium feeding the fœtal plasma sodium concentration did not stay constant but decreased. Joseph Dancis and Dawn Springer.Fetal Homeostasis in Maternal Malnutrition: Potassium and Sodium Deficiency in Rats Pediatric Research (1970) 4, 345–351; doi:10.1203/00006450 For prematures the mean potassium value is significantly higher in the lowest weight group, which could be related to the fact that high potassium concentrations are vital for the fœtus. Dietary potassium in sows during-pre-farrowing till weaning gave a numerical increase in the number of piglets born alive. Furthermore, the number of weaned piglets per sow and the total weight of weaned piglets per sow were significantly increased Christian Lückstädt and Kai-Jens Kühlmann. Dietary potassium diformate in sows during pre-farrowing till weaning: Effects on piglet performance in Thailand. Tropentag 2013, Stuttgart, Germany, September 17-19, 2013 The renal potassium secretory channels are uniquely adapted for K retention early in life. In contrast to the high rates of K secretion observed in adult cortical conducting ducts, segments isolated from neonatal animals show no significant net K transport until after the third week of postnatal life Satlin LM. Developmental regulation of expression of renal potassium secretory channels. Curr Opin Nephrol Hypertens. 2004;13:445–450. Normal blood serum sodium levels are 135-145 mEq/L, thus 50 times higher than for potassium. In milk however potassium levels (13 mEq/L) are 3 times higher than sodium (4 mEq/L). This may explain why milk has antimicrobial and anti-inflammatory properties. In human milk the potassium concentrations decrease between 3 and 18 week postpartum from 15.2 to 13.3 mEq/l. Already in 1952 it was found that milk had a suppressive effect on Plasmodium berghei in rat. The effect was not affected by changes in vitamin content, iron content, congelation or pasterurisation. As the authors state it seems clear that milk contains something that can inhibit or restrict the development of the asexual phase B. G. Maegraith, T. Deegan and E. Sherwood Jones. Suppression Of Malaria (P. Berghei) By Milk.British Medical Journal, 1952, Dec 27, 1382-1384). In young and premature infants the upper limit for hyperkalemia may be considerably higher, up to 6.5 mEq/L. Infant metabolisms use more potassium per day than adults. A baby needs to intake on average ar least 2 to 3 mEq/kg/day of potassium, compared to the 1 to 1,5 mEq/kg/d that adults require. The human being needs 4,700 milligrams of potassium each day, according to the Linus Pauling Institute. This recommendation starts at age 14 and is valid throughout the rest of life. The only time the need increases is while breast-feeding. In this case 5,100 milligrams on a daily basis are needed. Potassium keeps the skin moisturized and is effective against warts. Birthweight seems to be related to the inflammatory interleukin-1β. At a concentration of 100 pg/mL of IL-1β the birthweight is 1 500 grams and for 20 pg/mL it is 3000 grams. Interleukin-1β is an important cytokine produced in response to inflammatory stimuli. Potassium ion channels are involved in cytokine production by activated human macrophages Philippe Boeuf, Elizabeth H. Aitken, Upeksha Chandrasiri, Caroline Lin Lin Chua, Plasmodium falciparum Malaria Elicits Inflammatory Responses that Dysregulate Placental Amino Acid Transport.PLOS February 7, 2013http://dx.doi.org/10.1371/journal.ppat.1003153 M R Qiu, T J Campbell, A potassium ion channel is involved in cytokine production by activated human macrophages Clin Exp Immunol. 2002 Oct; 130(1): 67–74. Several studies from the University of Mainz show that potassium depletion triggers IL-1β maturation. This maturation was totally blocked when cells were suspended in medium that contained high K͘͘., but could be induced by replacing extracellular K with Na I Walev, K Reske, M Palmer, A Valeva, and S Bhakdi Potassium-inhibited processing of IL-1 beta in human monocytes. EMBO J. 1995 Apr 18; 14(8): 1607–1614.